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APP processing in Alzheimer's disease v1.0.1

APP processing in Alzheimer's disease

M1 muscarinic acetylcholine receptor in Alzheimer’s disease v1.0.0

This file encodes the article M1 muscarinic acetylcholine receptor in Alzheimer’s disease by Jiang et al, 2014

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers v1.0.0

This document contains the bel code for the Article Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers by De Felice et al

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro v1.0.0

This file encodes the article Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro by Nobuhara et. al. 2017

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage v1.0.0

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage from Shafiei et al., 2017

Tau oligomers and tau toxicity in neurodegenerative disease v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease by Ward et al., 2012

Tau Biochemistry v1.2.5

Tau Biochemistry Section of NESTOR

TAU and Interaction Partners v1.2.5

TAU Interactions Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

In-Edges 477

a(PUBCHEM:11249342) decreases p(HGNC:MAPT) View Subject | View Object

In addition, Posiphen significantly reduced levels of t-s (74.1%, as assessed by the Innogenetics assay and 46.2%, as assessed by the AlphaLisa assay) and p-s (61%, as assessed by the Innogenetics assay). PubMed:22791904

a(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT) View Subject | View Object

AD is characterized pathologically by the occurrence of intracellular neurofibrillary tangles rich in tau protein and extracellular plaques containing amyloid peptides (Price et al., 1991). PubMed:19293145

a(CHEBI:Anatabine) causesNoChange p(HGNC:MAPT) View Subject | View Object

No effect of the anatabine treatment was observed on tau expression (T-test, P>0.05) in Tg Tau P301S mice (Figure 4). DOI:10.4172/2168-975X.1000126

act(p(HGNC:CHRM1)) association act(p(HGNC:MAPT)) View Subject | View Object

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

a(GO:microtubule) association p(HGNC:MAPT) View Subject | View Object

In contrast, the neurofibrillary tangles are intracellular and are rich in tau, a structural protein that is normally associated with microtubuli PubMed:14556719

a(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT) View Subject | View Object

In contrast, the neurofibrillary tangles are intracellular and are rich in tau, a structural protein that is normally associated with microtubuli PubMed:14556719

a(MESH:"Neurofibrillary Tangles") increases p(HGNC:MAPT) View Subject | View Object

In conjunction with the formation of neurofibrillary tangles, the synthesis of the tau protein increases, and it undergoes an abnormal posttranslational modification characterized by hyperphosphorylation PubMed:14556719

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

a(PUBCHEM:675434) decreases p(HGNC:MAPT) View Subject | View Object

Treatment with IU1 reduced the levels of Tau, TDP-43, and ataxin-3 in MEFs in a USP14-dependent manner and independently of changes in proteasome levels or composition (147). PubMed:25784053

Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

p(HGNC:USP14) decreases deg(p(HGNC:MAPT)) View Subject | View Object

The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some; PubMed:25784053

Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

a(PUBCHEM:675434) increases deg(p(HGNC:MAPT)) View Subject | View Object

In a cell-based assay, IU1 treatment increased proteasomal activity to result in accelerated degradation rates of tau and oxidatively damaged proteins. PubMed:23528736

p(HGNC:MAPT, var("p.Ala152Thr")) causesNoChange p(HGNC:MAPT) View Subject | View Object

Moreover, the total expression levels of tau and PSD-95 were the same in 1-month-old neurons derived from control and patient iPSCs (Figure 1B) PubMed:27594586

g(DBSNP:rs63751011) causesNoChange p(HGNC:MAPT) View Subject | View Object

Moreover, the total expression levels of tau and PSD-95 were the same in 1-month-old neurons derived from control and patient iPSCs (Figure 1B) PubMed:27594586

a(CHEBI:"lithium(1+)") decreases p(HGNC:MAPT) View Subject | View Object

This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 . PubMed:30116051

a(CHEBI:"methylene blue") decreases act(p(HGNC:MAPT)) View Subject | View Object

Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin  1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 . PubMed:30116051

a(CHEBI:tanespimycin) decreases p(HGNC:MAPT) View Subject | View Object

The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 . PubMed:30116051

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 . PubMed:30116051

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Finally, while physiological tau possesses KFERQ motifs and is degraded by CMA, aggregates, mutant forms and frag- ments interfere with CMA 45,47 . PubMed:30116051

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:MAPT)) View Subject | View Object

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 . PubMed:30116051

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051

p(HGNC:CAST) increases deg(p(HGNC:MAPT)) View Subject | View Object

Calpain inhibition by cal- pastatin or pharmacological agents also confers neuropro- tective effects in other NDA models, including improved clearance of tau, α-synuclein and SOD1 (REFS54,106,107) . PubMed:30116051

p(HGNC:MAPT, pmod(HBP:HBP00007)) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051

p(HBP:HBP00053, var("p.Lys280del")) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Interestingly, a deletion of lysine 280 (hTau40 DK280), known to lead to tau aggregation (Khlistunova et al., 2006), turned this protein into a very poor CMA substrate (Fig. 6a,b) PubMed:29024336

a(CHEBI:"N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal") increases p(HGNC:MAPT) View Subject | View Object

In M1C neuroblastoma cells that inducibly express wild-type full-length tau (4R0N), EPX, and MG-132 induced accumulation of full-length tau but there was a concomitant loss of C-terminus immunoreactivity (64). PubMed:24027553

act(a(CHEBI:"Hsp90 inhibitor")) decreases p(HGNC:MAPT) View Subject | View Object

For example, treatment of primary neurons with an Hsp90 inhibitor to interrupt the proper chaperoning of tau leads to decreased levels of tau. Adding MG-132 to block the proteasome prevented the Hsp90 inhibitor-induced reduction in total tau. MG-132 alone had no effect on tau levels (67). PubMed:24027553

act(a(CHEBI:Thrombin)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Evidence supporting a role for thrombin in tau proteolysis came initially from an in vitro study showing that thrombin degraded recombinant full-length tau from the N-terminus yielding a 25-kDa fragment, while preserving the microtubule binding repeat domain (13). PubMed:24027553

act(a(CHEBI:Thrombin)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553

a(CHEBI:chloroquine) increases p(HGNC:MAPT) View Subject | View Object

Treating hippocampal slices with chloroquine (CQ), which raises the pH of lysosomes to impair enzymatic function, was associated with increased levels of full-length tau (89, 91). PubMed:24027553

a(CHEBI:chloroquine) decreases deg(p(HGNC:MAPT)) View Subject | View Object

In M1C neuroblastoma cells that inducibly express full-length wild-type tau (4R0N), treatment with CQ also significantly slowed down tau degradation, and caused its accumulation (92). Treatment of hippocampal slices with the cathepsin modulator ZPAD (which stimulates cathepsin D very strongly) appears to increase the proteolysis of full-length tau resulting in the production of smaller fragments, including a phosphorylated 29 kDa fragment (86, 89). This partial degradation of tau was inhibited by inclusion of a selective cathepsin D inhibitor (86). PubMed:24027553

a(CHEBI:epoxomicin) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Similarly, overexpressing the FTDP-17 mutant P301L tau in SH-SY5Y cells and then treating with lactacystin led to significantly increased tau levels (70). Lactacystin also caused accumulation of endogenous tau in the HT22 murine neuronal cell line (71). In immortalized mouse cortical neuronal cells inducibly expressing full-length wild-type tau, EPX slowed the degradation of full-length tau (72). PubMed:24027553

a(CHEBI:epoxomicin) increases p(HGNC:MAPT) View Subject | View Object

In M1C neuroblastoma cells that inducibly express wild-type full-length tau (4R0N), EPX, and MG-132 induced accumulation of full-length tau but there was a concomitant loss of C-terminus immunoreactivity (64). PubMed:24027553

a(CHEBI:lactacystin) decreases deg(p(HGNC:MAPT)) View Subject | View Object

In SH-SY5Y neuroblastoma cells, treatment with lactacystin, a selective inhibitor of the 20S catalytic core, maintained levels of transfected wild-type full-length tau (4R0N) after cycloheximide treatment halted protein synthesis (65). PubMed:24027553

a(CHEBI:lactacystin) increases p(HGNC:MAPT) View Subject | View Object

Additionally, incubation of rat brain extract (containing endogenous tau and proteasomal enzymes) with the proteasome activators Mg2+ and ATP resulted in lower total tau levels with an increase in smaller forms, compared to extract not supplemented with Mg2+ and ATP (73). The loss of tau was blocked by lactacystin giving further evidence that the proteasome was degrading tau (73). PubMed:24027553

act(a(MESH:"Proteasome Endopeptidase Complex")) increases deg(p(HGNC:MAPT)) View Subject | View Object

Not surprisingly, if recombinant tau is incubated with isolated 20S proteasomal complexes, degradation occurs (65). In this system proteolysis is bidirectional. Also, if tau is first ubiquitylated in an in vitro reaction and then incubated with isolated 26S proteasomes supplemented with MgCl2 and ATP, degradation proceeds (66). These data indicate tau can be a substrate for both forms of the proteasome. PubMed:24027553

a(MESH:Trehalose) decreases p(HGNC:MAPT) View Subject | View Object

In a cell line expressing the repeat domain of tau containing the FTDP-17ΔK280 mutant, treatment with the disaccharide trehalose, an mTor-independent autophagy activator, significantly reduced aggregated tau as measured by Thioflavin-S staining, as well as total tau levels both soluble and insoluble as detected by western blotting (96). PubMed:24027553

bp(GO:autophagy) association deg(p(HGNC:MAPT)) View Subject | View Object

PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553

bp(MESH:Autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

Directly activating autophagy through a variety of mechanisms leads consistently to enhanced tau clearance – either pathological forms or total tau. In a hippocampal slice preparation methylene blue was used to induce autophagy, which resulted in a decrease in phosphorylated tau and insoluble tau, specifically (95). PubMed:24027553

bp(MESH:Autophagy) causesNoChange p(HGNC:MAPT) View Subject | View Object

Additionally, in a hippocampal slice preparation, induction of autophagy by treatment with methylene blue led to a decrease in phosphorylated tau and insoluble tau without an effect on total tau (95). PubMed:24027553

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Additionally, incubation of rat brain extract (containing endogenous tau and proteasomal enzymes) with the proteasome activators Mg2+ and ATP resulted in lower total tau levels with an increase in smaller forms, compared to extract not supplemented with Mg2+ and ATP (73). The loss of tau was blocked by lactacystin giving further evidence that the proteasome was degrading tau (73). PubMed:24027553

p(HGNCGENEFAMILY:Proteasome) increases deg(p(HGNC:MAPT)) View Subject | View Object

This is supported by evidence that full-length tau, which has a lower propensity for aggregating, is cleared by the proteasome while caspase- cleaved tau, which is more aggregate prone, goes through autophagy (72). Also, aggregated tau can be cleared by inducing autophagy (70, 96). PubMed:24027553

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Soluble, monomeric tau is an ideal proteasomal substrate. Indeed, it has been clearly demonstrated that tau can be degraded by the proteasome (65–67, 73). It thus can be suggested that under physiologic circumstances much of tau is degraded in this manner, with select modified forms being cleared by autophagy.However, within the context of the AD milieu, additional tau modifications and degradative impairments may cause the balance to shift away from proteasomal degradation toward autophagy. PubMed:24027553

p(HGNC:CTSD) increases deg(p(HGNC:MAPT)) View Subject | View Object

Cathepsin D, a lysosomal protease, exhibited the capacity to degrade tau proteins in cultured hippocampal slices (Bednarski and Lynch, 1996). PubMed:23528736

act(p(HGNC:CASP3)) increases deg(p(HGNC:MAPT)) View Subject | View Object

There may be reciprocity with the apoptosis pathway as activating caspase-3 by inducing apoptosis in cortical neuronal culture led to tau cleavage (22), and selectively expressing tauC3 led to apoptosis in NT2 and COS cells (21). This might represent a feed-forward loop of neurotoxicity. PubMed:24027553

composite(p(HGNC:CTSD), p(HGNC:MAPT)) decreases p(HGNC:MAPT) View Subject | View Object

Incubation of tau with cathepsin D at pH 4.0 resulted in a decrease in full-length tau and a concomitant increase in cleaved fragments of varying sizes (89). PubMed:24027553

composite(p(HGNC:CTSD), p(HGNC:MAPT)) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Incubation of tau with cathepsin D at pH 4.0 resulted in a decrease in full-length tau and a concomitant increase in cleaved fragments of varying sizes (89). PubMed:24027553

act(p(HGNC:CTSD)) increases deg(p(HGNC:MAPT)) View Subject | View Object

In M1C neuroblastoma cells that inducibly express full-length wild-type tau (4R0N), treatment with CQ also significantly slowed down tau degradation, and caused its accumulation (92). Treatment of hippocampal slices with the cathepsin modulator ZPAD (which stimulates cathepsin D very strongly) appears to increase the proteolysis of full-length tau resulting in the production of smaller fragments, including a phosphorylated 29 kDa fragment (86, 89). This partial degradation of tau was inhibited by inclusion of a selective cathepsin D inhibitor (86). PubMed:24027553

act(p(HGNC:CTSD)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Cathepsin D seems particularly important for degrading tau, as its expression was neuroprotective in a Drosophila tauopathy model. Levels of cathepsin D are elevated in flies expressing mutant human tau. If cathepsin D is genetically ablated, these tau flies exhibit enhanced neurotoxicity and a shorter lifespan (93). PubMed:24027553

act(p(HGNC:HTRA1)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553

act(p(HGNC:HTRA1)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Tubulin was later identified as a substrate for HTRA1, suggesting HTRA1 may be involved in mediating microtubule function (42, 43). A more recent study showed that HTRA1 can cleave recombinant tau in vitro into multiple fragments of varying sizes, and furthermore can degrade insoluble and fibrillarized tau (16). PubMed:24027553

p(HGNC:NPEPPS) decreases p(HGNC:MAPT) View Subject | View Object

In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12). PubMed:24027553

p(HGNC:NPEPPS) regulates deg(p(HGNC:MAPT)) View Subject | View Object

For example, it has been shown that the isomerase Pin1, which has been implicated in AD (30), had opposite effects on P301L and wild-type tau degradation (31). An alternative explanation for the effects of PSA may be that PSA is indirectly regulating tau degradation. PubMed:24027553

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

act(p(HGNCGENEFAMILY:Aminopeptidases)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553

act(p(HGNCGENEFAMILY:Calpains)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553

act(p(HGNCGENEFAMILY:Calpains)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Excitotoxicity leading to elevated intracellular calcium is a common feature of neurodegenerative diseases, and is implicated in AD (49, 50). This process may lead to enhanced activation of calpains (51). This in turn could influence a number of pathologic processes, including tau proteolysis. Indeed, tau has a number of putative calpain cleavage sites, and incubation of recombinant tau with calpain generates specific fragments, including one that is ∼35 kDa and one that is ∼17 kDa (19, 20). PubMed:24027553

act(p(HGNCGENEFAMILY:Calpains)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Increasing intracellular calcium levels in PC12 cells leads to calpain-induced cleavage of tau (18). This may reflect a potential effect of excitotoxicity in AD. Inducing apoptosis in cerebellar granule cells yields calpain-mediated tau fragments, including a dominant ∼17 kDa fragment (17). PubMed:24027553

Annotations
Experimental Factor Ontology (EFO)
PC12
Text Location
Review

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Even though the modifications of tau that are the primary contributors to toxicity have not been conclusively determined, it is clear that tau plays an essential role in the pathogenesis of AD. PubMed:24027553

act(p(HGNCGENEFAMILY:Caspases)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Also of importance is understanding the role of non-degradative cleavage in influencing the eventual clearance of tau. Numerous proteases have been shown to proteolyze tau including aminopeptidases (10–12), thrombin (13–15), human high temperature requirement serine protease A1 (HTRA1) (16), calpain (17–20), and caspases (21–24). PubMed:24027553

act(p(HGNCGENEFAMILY:Caspases)) increases deg(p(HGNC:MAPT)) View Subject | View Object

There is significant evidence that tau is a caspase substrate and that caspase-mediated tau cleavage may play a role in AD pathology. Early in vitro studies demonstrated that tau is cleaved in the C-terminus by several caspases including caspase-3 and caspase-6 (21–23). PubMed:24027553

act(p(HGNCGENEFAMILY:Caspases)) increases deg(p(HGNC:MAPT)) View Subject | View Object

First, inflammation, which is a common feature of AD, may contribute to tau pathology by activating caspases. Treating cells with the prostaglandin cyclopentenone byproduct PGJ2 increased caspase activity and increased cleaved tau (62). PubMed:24027553

a(GO:"Pick body") association p(HGNC:MAPT) View Subject | View Object

Similarly, the characteristic Pick bodies in the frontal cortex were well labeled by TNT1, TOC1 and R1 in PiD tissue (Fig. 5M–P) PubMed:27574109

a(HBP:"Braak_Stage I") association p(HGNC:MAPT) View Subject | View Object

Indeed, early pre-tangle neurons within the hippocampus were labeled with all antibodies in Braak I-II cases (Fig. 5A–D) PubMed:27574109

a(HBP:"Braak_Stage II") association p(HGNC:MAPT) View Subject | View Object

Indeed, early pre-tangle neurons within the hippocampus were labeled with all antibodies in Braak I-II cases (Fig. 5A–D) PubMed:27574109

a(HBP:"Corticobasal Degeneration") association p(HGNC:MAPT) View Subject | View Object

In CBD, the characteristic astrocytic pathology (e.g. astrocytic plaques) showed extensive co-localization between TNT1, TOC1 and R1 in the frontal cortex (Fig. 5I–L). PubMed:27574109

a(HBP:"Corticobasal Degeneration") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the soluble fractions were similar for AD, CBD and PiD, as indicated by the Tau5 sandwich ELISA (Fig. 6B; one-way ANOVA, F(2,9) = 3.283, p = 0.085) PubMed:27574109

a(HBP:"Corticobasal Degeneration") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the insoluble fractions, as detected by Tau5, were highest in AD, followed by CBD and PiD contained the least (Fig. 6E; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 25.93, p = 0.0002) PubMed:27574109

a(HBP:pretangles) association p(HGNC:MAPT) View Subject | View Object

Indeed, early pre-tangle neurons within the hippocampus were labeled with all antibodies in Braak I-II cases (Fig. 5A–D) PubMed:27574109

a(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT) View Subject | View Object

In severe AD cases (i.e. Braak stage V-VI), all markers continue to colocalize in classic NFTs within the hippocampus that characterize AD tau pathology (Fig. 5E–H) PubMed:27574109

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the soluble fractions were similar for AD, CBD and PiD, as indicated by the Tau5 sandwich ELISA (Fig. 6B; one-way ANOVA, F(2,9) = 3.283, p = 0.085) PubMed:27574109

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the insoluble fractions, as detected by Tau5, were highest in AD, followed by CBD and PiD contained the least (Fig. 6E; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 25.93, p = 0.0002) PubMed:27574109

path(MESH:"Pick Disease of the Brain") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the soluble fractions were similar for AD, CBD and PiD, as indicated by the Tau5 sandwich ELISA (Fig. 6B; one-way ANOVA, F(2,9) = 3.283, p = 0.085) PubMed:27574109

path(MESH:"Pick Disease of the Brain") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the insoluble fractions, as detected by Tau5, were highest in AD, followed by CBD and PiD contained the least (Fig. 6E; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 25.93, p = 0.0002) PubMed:27574109

p(HGNC:MAPT) increases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Internalization of monomeric tau (P301S) and wild-type tau was comparable and concentration dependent (Figure S3A), confirming that the P301S mutation does not confer the ability to efficiently enter neurons, nor is this form of tau likely to aggregate in extracellular media during the 3- to 4-hr incubation period PubMed:29590627

a(CHEBI:"latrunculin A") decreases p(HGNC:MAPT) View Subject | View Object

Latrunculin treatment produced rapid actin depolymerization and the corresponding disappearance of LifeAct-RFP fluorescence in every spine studied; no synaptic EGFP-tau fluorescence was observed (data not shown). PubMed:24760868

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, loc(MESH:"Post-Synaptic Density")) View Subject | View Object

Abetao exposure induced a translocation of tau into the PSD fraction (***p  0.0002, 2-tailed Student’s t test; control 20.12  1228 vs Abetao 29.74  1.748, N  12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10  2.557 vs Abetao 33.3  2153, N  9 independent culture), GluA1 (**p  0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p  0.0041, 2-tailed Student’s t test; control 19.42  1.337 vs Abetao 29.67  2.181, N  6 independent cultures; Fig. 6D). PubMed:24760868

a(HBP:"amyloid-beta oligomers") decreases p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

After Abetao treatment, synaptic activation did not trigger any increase in synaptic markers and in fact decreased synaptic actin (***p  0.0009, 2-tailed Student’s t test; Abetao 29.64  1.495, Abetao Bic/4-AP 18.56 2.030, N  7 independent cultures; Fig. 7C), PSD-95 (***p0.0007, 2-tailed Student’s t test; Abetao 33.37  2.153, Abetao Bic/4-AP 19.25 2.550, N  7 independent cultures) and tau levels (**p0.0014, 2-tailed Student’s t test; Abetao 29.74 1.748, Abetao Bic/4-AP 20.68 1.751, N  12 independent cultures). PubMed:24760868

a(HBP:"amyloid-beta oligomers") increases tloc(p(HGNC:MAPT)) View Subject | View Object

When we investigated Abetao-driven tau translocation to the synapse, we did not see any change in half-life recovery (4.729 s) from those measured with synaptic activation. However, the plateau value was drastically modified (71.20%), illustrating that, whereas Abetao induced tau translocation and subsequently its interaction with actin filament, the resulting synaptic tau is less stable. PubMed:24760868

a(MESH:jasplakinolide) increases p(HGNC:MAPT) View Subject | View Object

For this, we treated our primary cortical neurons with jasplakinolide (1 M), a compound that promotes actin polymerization (Lazaro- Dieguez et al., 2008), or with a latrunculin A (at 500 nM), a compound that depolymerizes F-actin into soluble globular actin (Gactin; Coue´ et al., 1987; Fig. 5C). After jasplakinolide application, we observed a large increase in synaptic EGFP-tau fluorescence PubMed:24760868

a(MESH:"Dendritic Spines") association tloc(p(HGNC:MAPT)) View Subject | View Object

The recovery curves indicated 3 pools of tau: a mobile, unbleached fraction comprising 9.72  1.03%, a dynamic fraction at 47.08  3.06%, and a stable, unrecoverable fraction at 42.75  2.78%. This stable fraction suggests that a large portion of tau is anchored in the spine. PubMed:24760868

a(MESH:"Dendritic Spines") association p(HGNC:MAPT) View Subject | View Object

The recovery curves indicated 3 pools of tau: a mobile, unbleached fraction comprising 9.72  1.03%, a dynamic fraction at 47.08  3.06%, and a stable, unrecoverable fraction at 42.75  2.78%. This stable fraction suggests that a large portion of tau is anchored in the spine. PubMed:24760868

bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

Therefore, during a long-lasting synaptic activation, we observed an increase in tau, fyn, actin, GluA1, and PSD-95 content in the PSD-positive fraction, which is consistent with the characteristic features of synaptic plasticity (Ehlers, 2003). PubMed:24760868

bp(GO:"long-term synaptic potentiation") positiveCorrelation tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) View Subject | View Object

These results suggest that tau translocates from the dendritic shaft to the synapse during activation and probably takes part in the activity-driven synaptic reorganization that underlies synaptic plasticity PubMed:24760868

bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

We observed a similar LTPinduced increase in tau content within the PSD-enriched fraction from CA1 synaptosomes (29.86 +-4.86 to 70.15 +- 4.86, **p = 0.0011; Fig. 3B). As expected, actin and GluA1 were also increased, strengthening the idea that tau is involved in synaptic reorganization processes necessary for synaptic plasticity PubMed:24760868

bp(MESH:"Neuronal Plasticity") association tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) View Subject | View Object

These results suggest that tau translocates from the dendritic shaft to the synapse during activation and probably takes part in the activity-driven synaptic reorganization that underlies synaptic plasticity PubMed:24760868

complex(GO:"filamentous actin") association p(HGNC:MAPT) View Subject | View Object

These results show that the amount of tau collected is proportional to neuronal F-actin content, suggesting a close link between F-actin and tau. PubMed:24760868

complex(GO:"filamentous actin") increases p(HGNC:MAPT) View Subject | View Object

We analyzed actin and tau in the PSD-enriched fraction from primary cortical neurons treated with jasplakinolide (Fig. 5E). We observed that increased neuronal F-actin content promotes concurrent tau enrichment (*p0.0150, 2-tailed Student’s t test; control 17.49  0.7755 vs jasplakinolide 27.02  2719, N  4 independent cultures; Fig. 5F). GLUA1, the membrane trafficking of which is known to be actin dependent, was increased (*p 0.0279, 2-tailed Student’s t test; control 16.91  1015 vs jasplakinolide 31.00  4.778, N  4 independent cultures). The amount of Fyn in the PSD was decreased (*p  0.0265, 2-tailed Student’s t test; control 27.25 5.003 vs jasplakinolide 11.71  1.786, N  4 independent cultures). PubMed:24760868

complex(GO:"filamentous actin") increases p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

Together, these results suggest that tau translocation to the synapse depends on the F-actin stabilization that promotes their interaction. PubMed:24760868

p(HGNC:MAPT, pmod(Ph)) association act(p(HGNC:MAPT)) View Subject | View Object

Conversely, only Abetao exposure promoted significant tau phosphorylation on Ser 404 (**p0.05, 1-way ANOVA; control 15.672.418 vs Abetao 32.65  3.76 vs Bic/4-AP 26.75  1.17 vs Abetao Bic/4-AP 24.97  4.48, N  4). These results revealed that, although synaptic activation or Abetao promote tau translocation to PSD fractions, the synaptic tau displays a different phosphorylation profile that may be responsible for the conditional tau properties observed. PubMed:24760868

p(HGNC:MAPT, pmod(Ph, Ser, 404)) increases p(HGNC:MAPT, loc(MESH:"Dendritic Spines")) View Subject | View Object

We observed that synaptic activation promoted EGFP-Tau T205A translocation to the spine but FRAP experiments revealed a shorter tau turnover time in the spine (Fig. 9B), whereas Abetao driven translocation to the spine was no longer observable in EGFP-Tau S404A-transfected neurons (Fig. 9F,G). These experiments highlight the pivotal role of these phosphorylations in tau translocation features to the spine. PubMed:24760868

p(HGNC:MAPT, pmod(Ph, Thr, 205)) increases p(HGNC:MAPT, loc(MESH:"Dendritic Spines")) View Subject | View Object

We observed that synaptic activation promoted EGFP-Tau T205A translocation to the spine but FRAP experiments revealed a shorter tau turnover time in the spine (Fig. 9B), whereas Abetao driven translocation to the spine was no longer observable in EGFP-Tau S404A-transfected neurons (Fig. 9F,G). These experiments highlight the pivotal role of these phosphorylations in tau translocation features to the spine. PubMed:24760868

a(CHEBI:"lithium atom") decreases p(HGNC:MAPT) View Subject | View Object

and lithium (Shimada et al., 2012) in human tau over-expressing Tg mice induced autophagy, which is accompanied by the reduced levels of pathological tau and NFT formation in tauopathy model mice. PubMed:23528736

a(CHEBI:"methylene blue") decreases p(HGNC:MAPT) View Subject | View Object

Methylene blue, which has been known to directly inhibit tau aggregation, is also capable to induce autophagy and reduce total and phospho-tau levels with improved cognitive performance in tau transgenic mice by oral administration (Congdon et al., 2012). PubMed:23528736

a(CHEBI:epoxomicin) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(CHEBI:lactacystin) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(CHEBI:leupeptin) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(CHEBI:sirolimus) increases deg(p(HGNC:MAPT)) View Subject | View Object

Autophagy inducers, including rapamycin (Fig. 3A), facilitate the degradation of insoluble forms of tau and also protect against its toxicity in Drosophila (Berger et al., 2006). PubMed:23528736

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT) View Subject | View Object

Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008). PubMed:23528736

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association deg(p(HGNC:MAPT)) View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system. PubMed:23528736

composite(p(HGNC:HSPA8), p(HGNC:STUB1), p(HGNC:UBE2D2)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Further evidence of UPS-mediated tau degradation came from the identification of the tau E3 ligase, which is the carboxyl terminus of the Hsc70–interacting protein (CHIP)–Hsc70 complex, with UbcH5B as the E2 enzyme (Petrucelli et al., 2004; Shimura et al., 2004). PubMed:23528736

act(p(FPLX:mTORC1)) increases p(HGNC:MAPT) View Subject | View Object

The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736

a(CHEBI:"Hsp90 inhibitor") increases deg(p(HGNC:MAPT)) View Subject | View Object

For example, Hsp90 inhibitors cause degradation of tau and many cancer-related substrates [85]. PubMed:21882945

bp(GO:aging) negativeCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

Interestingly, tau clearance is known to be impaired in the aging brain [45], supporting the idea that diminished quality control might be conducive to certain tauopathies, such as AD, which are linked to aging PubMed:21882945

bp(HBP:Proteostasis) regulates p(HGNC:MAPT) View Subject | View Object

All proteins, including tau, are subject to extensive regulation by the cellular quality control pathways, which carefully control the balance between protein expression and turnover to maintain healthy protein homeostasis (or proteostasis) PubMed:21882945

p(HGNC:HSPB1) increases p(HGNC:MAPT) View Subject | View Object

However, astrocyte-derived Hsp27 has been shown to promote tau accumulation and Hsp27 associates with tau tangles in a mouse model [127,128], suggesting a more complex relationship PubMed:21882945

p(HGNC:HSPB1) decreases p(HGNC:MAPT) View Subject | View Object

Recently, our group demonstrated that viral delivery of wild-type Hsp27 into the brains of tau-transgenic mice reduced tau levels and rescued long-term potentiation deficits. PubMed:21882945

act(p(INTERPRO:"Heat shock protein 70 family")) increases deg(p(HGNC:MAPT)) View Subject | View Object

In fact, recent work from our group has shown that inhibition of the ATPase activity of Hsp70/Hsc70 promotes proteasomal degradation of tau; whereas activation results in tau accumulation [117] PubMed:21882945

act(p(INTERPRO:"Heat shock protein 70 family")) increases p(HGNC:MAPT) View Subject | View Object

The fact that Hsp70 inhibitors reduce tau levels without affecting other likely Hsp70 substrates, such as a-synuclein or TDP-43, generally supports the idea that substrates are actively involved in dictating their own fate [117] PubMed:21882945

p(HGNC:FKBP5) increases p(HGNC:MAPT) View Subject | View Object

These interactions may be functionally important because silencing FKBP51 reduces tau and phosphorylated-tau levels [136]. PubMed:21882945

p(HGNC:BAG1) decreases deg(p(HGNC:MAPT)) View Subject | View Object

BAG1 silencing decreases tau levels, consistent with a critical role for this co-chaperone in protecting tau from degradation. PubMed:21882945

complex(p(HGNC:BAG1), p(INTERPRO:"Heat shock protein 70 family")) increases p(HGNC:MAPT) View Subject | View Object

BAG1 is upregulated in the hippocampus of AD patients [130], where it associates with tau and increases tau levels in cooperation with Hsp70 [131] PubMed:21882945

complex(p(HGNC:STUB1), p(INTERPRO:"Heat shock protein 70 family")) increases deg(p(HGNC:MAPT)) View Subject | View Object

Hsp70 has been shown to both stabilize binding of tau to microtubules [114] and promote its degradation in combination with CHIP [115,116] PubMed:21882945

p(HGNC:AKT1) negativeCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

Interestingly, it was recently found that reducing the levels of Akt, another client of the Hsp90/CHIP complex, facilitates tau degradation [123], suggesting a synchronized balance between competing Hsp90 substrates that may be driven, in part, by their relative abundance or susceptibility to Hsp90 binding PubMed:21882945

act(p(HGNC:HSPA8)) increases deg(p(HGNC:MAPT)) View Subject | View Object

In fact, recent work from our group has shown that inhibition of the ATPase activity of Hsp70/Hsc70 promotes proteasomal degradation of tau; whereas activation results in tau accumulation [117] PubMed:21882945

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037

path(MESH:"Brain Injuries, Traumatic") association p(HGNC:MAPT) View Subject | View Object

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037

path(MESH:"Supranuclear Palsy, Progressive") association p(HGNC:MAPT) View Subject | View Object

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037

a(HBP:"Tau antibody, 40E8") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, 40E8") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

a(HBP:"Tau antibody, 40E8") decreases p(HGNC:MAPT) View Subject | View Object

for example, the two phosphorylation dependent tau antibodies (40E8 and p396) were the most efficient in the human AD case with the highest level of phosphorylated tau (1266). Both 6C5 and 40E8, shown to be most effective at reducing uptake from HMW human AD brainederived tau species (Figure 3, B and C), immunostained NFTs and neuritic plaques in postmortem human AD frontal cortex sections (Figure 6); 40E8 was somewhat more reactive to neuropil threads under the conditions used. PubMed:28408124

a(HBP:"Tau antibody, 4E4") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, 4E4") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

a(HBP:"Tau antibody, 6C5") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, 6C5") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

a(HBP:"Tau antibody, 6C5") decreases p(HGNC:MAPT) View Subject | View Object

for example, the two phosphorylation dependent tau antibodies (40E8 and p396) were the most efficient in the human AD case with the highest level of phosphorylated tau (1266). Both 6C5 and 40E8, shown to be most effective at reducing uptake from HMW human AD brainederived tau species (Figure 3, B and C), immunostained NFTs and neuritic plaques in postmortem human AD frontal cortex sections (Figure 6); 40E8 was somewhat more reactive to neuropil threads under the conditions used. PubMed:28408124

a(HBP:"Tau antibody, 6C5") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

This result is consistent with the idea that the 6C5 antibody can slow tau uptake even after neurons have been exposed to the pathological tau and the uptake process initiated. PubMed:28408124

a(HBP:"Tau antibody, HT7") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, HT7") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

a(HBP:"Tau antibody, Tau-13") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, Tau-13") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

a(HBP:"Tau antibody, Tau46") causesNoChange tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

Tau46 was the only antibody that did not show a statistically significant reduction in neuronal tau uptake (Figure 4, B and C). Tau46 bound with high apparent affinity to both recombinant and paired helical filament tau by ELISA (Table 2), demonstrating the binding of the antibody to full-length tau. PubMed:28408124

a(HBP:"Tau antibody, Tau46") association p(HGNC:MAPT) View Subject | View Object

Tau46 was the only antibody that did not show a statistically significant reduction in neuronal tau uptake (Figure 4, B and C). Tau46 bound with high apparent affinity to both recombinant and paired helical filament tau by ELISA (Table 2), demonstrating the binding of the antibody to full-length tau. PubMed:28408124

a(HBP:"Tau antibody, pS396") decreases p(HGNC:MAPT, loc(GO:cell)) View Subject | View Object

Tau13, 6C5, and HT7 efficiently depleted tau from the AD HMW fraction (97%, 82%, and 72%, respectively), whereas the other four antibodies (40E8, 4E4, p396, and Tau46) removed only a small fraction of tau (33%, 4.7%, 22%, and 21% reductions, respectively) (Figure 4A). PubMed:28408124

a(HBP:"Tau antibody, pS396") decreases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In the tau uptake assay, 6C5 most effectively reduced tau uptake by immunodepletion (75% reduction) (Figure 4, B and C). Tau13 and HT7 showed intermediate effects (55% and 47% reductions, respectively) (Figure 4, B and C). The 40E8, p396, and 4E4 antibodies also reduced neuronal tau uptake (65%, 53%, and 47% reductions, respectively), despite their low immunodepletion efficiency (Figure 4). PubMed:28408124

p(HGNC:AK1) increases act(p(HGNC:MAPT)) View Subject | View Object

Co-expression of an AK1 transgene with tau in flies (gl-tau2.1/UAS-AK1) markedly enhanced tau-induced retinal degeneration,indicating that AK1 enhances tau toxicity in the fly retina. PubMed:22419736

path(MESH:"Alzheimer Disease") causesNoChange p(HGNC:MAPT) View Subject | View Object

Interestingly, the phosphorylated form of tau at Ser 396/404 (PHF-1) was detected exclusively in AD patients, although total amounts of tau protein (TG5) were not changed PubMed:22419736

a(GO:microvesicle) association sec(p(HGNC:MAPT)) View Subject | View Object

Recently, more evidence implies that the secretion of tau occurs through unconventional cellular pathways via vesicles known as exosomes (Saman et al., 2012) and ectosomes (Dujardin et al., 2014a) PubMed:28420982

a(GO:microvesicle) regulates sec(p(HGNC:MAPT)) View Subject | View Object

Significantly, evidence suggests that tau secretion is partly mediated by ectosomal vesicles and that pathological tau accumulation in cells leads to a deviation toward tau secretion by exosomal vesicles (Dujardin et al., 2014a) PubMed:28420982

a(HBP:"Tau aggregates") association sec(p(HGNC:MAPT)) View Subject | View Object

Significantly, evidence suggests that tau secretion is partly mediated by ectosomal vesicles and that pathological tau accumulation in cells leads to a deviation toward tau secretion by exosomal vesicles (Dujardin et al., 2014a) PubMed:28420982

a(HBP:"Tau oligomers") increases tloc(p(HGNC:MAPT), fromLoc(GO:"neuron part"), toLoc(GO:"neuron part")) View Subject | View Object

With this concept, tau may be able to translocate between neurons and augment toxic tau components; in fact, evidence suggests probability of tau oligomer propagation between synaptically connected neurons (Gendreau and Hall, 2013; Pooler et al., 2013b) PubMed:28420982

p(HGNC:CDC37) increases p(HGNC:MAPT) View Subject | View Object

Interestingly, overexpression of Cdc37 preserves tau, and its suppression reduces tau (Jinwal et al., 2012). PubMed:29311797

a(MESH:"Heparan Sulfate Proteoglycans") increases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular space"), toLoc(GO:"intracellular part")) View Subject | View Object

In other words, the HSPGs serve as a receptor for the cellular uptake of tau, a critical step similar to prion-like propagation PubMed:28420982

a(MESH:Exosomes) association sec(p(HGNC:MAPT)) View Subject | View Object

Recently, more evidence implies that the secretion of tau occurs through unconventional cellular pathways via vesicles known as exosomes (Saman et al., 2012) and ectosomes (Dujardin et al., 2014a) PubMed:28420982

bp(GO:"intracellular signal transduction") association p(HGNC:MAPT) View Subject | View Object

This hints that tau plays a role in monitoring intracellular signaling pathways (Pooler and Hanger, 2010) PubMed:28420982

bp(GO:behavior) association p(HGNC:MAPT) View Subject | View Object

While evidence has linked FTD with parkinsonism in patients to tau mutations on chromosome 17 (FTDP-17), implying that tau dysfunction alone can cause neurodegeneration (Reed et al., 2001), studies in animal models have shown that overexpression of tau can lead to cell death (Lee et al., 2001; Tanemura et al., 2001, 2002; Tatebayashi et al., 2002) and exhibit behavioral abnormalities and synaptic dysfunction without the presence of NFTs (Wittmann et al., 2001; Andorfer et al., 2003; Santacruz et al., 2005; Spires et al., 2006; Berger et al., 2007; Yoshiyama et al., 2007; Cowan et al., 2010) PubMed:28420982

bp(HP:Neurodegeneration) decreases sec(p(HGNC:MAPT)) View Subject | View Object

Recently, tau was discovered in the interstitial fluid of awake, wild-type mice, suggesting its release by neurons in the absence of neurodegeneration (Yamada et al., 2011) PubMed:28420982

bp(MESH:"Neuronal Plasticity") increases tloc(p(HGNC:MAPT), fromLoc(GO:cell), toLoc(GO:cell)) View Subject | View Object

A recent study showed that neuronal networks facilitate cell-to-cell transfer of tau via synapses; using a microfluidic device they demonstrated that decreasing synaptic connections weakens tau transfer and the subsequent aggregation on the acceptor cell (Calafate et al., 2015) PubMed:28420982

bp(MESH:Aging) association tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(GO:"cell body")) View Subject | View Object

Further, transgenic mouse lines expressing human tau aggregates in the entorhinal cortex have shown that tau is mislocalized from axons to cell bodies and dendrites as the mice age (Pooler et al., 2013b) PubMed:28420982

bp(MESH:Aging) association tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(GO:dendrite)) View Subject | View Object

Further, transgenic mouse lines expressing human tau aggregates in the entorhinal cortex have shown that tau is mislocalized from axons to cell bodies and dendrites as the mice age (Pooler et al., 2013b) PubMed:28420982

complex(a(GO:vesicle), a(MESH:"Cell Membrane")) increases sec(p(HGNC:MAPT)) View Subject | View Object

In the latter theory, during the secretion, vesicles and the cell membrane can be fused and uncoated tau protein can be released to the extracellular space (Clavaguera et al., 2009; Iba et al., 2013) PubMed:28420982

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

In AD, the quantity of tau identified in the CSF increases with disease progression (Hampel et al., 2010). However, the mechanism of tau propagation from the brain to the CSF remains elusive PubMed:28420982

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT) View Subject | View Object

In AD, tau pathology has been found to spread from the transentorhinal cortex to the neocortex in a sequential pathway PubMed:28420982

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

path(MESH:"Frontotemporal Dementia") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

a(CHEBI:"withaferin A") decreases p(HGNC:MAPT) View Subject | View Object

The Cdc37/Hsp90 inhibitors, Celasterol and Withaferin A (Zhang et al., 2008; Yu et al., 2010), reduce tau levels and a new compound, platycodin D has just been discovered (Li et al., 2017). Platycodin D does not affect the ATPase activity of Hsp90, but instead disrupts the interaction between Hsp90 and Cdc37 leading to client protein degradation without an increase in Hsp70 (Li et al., 2017). PubMed:29311797

a(CHEBI:celastrol) decreases p(HGNC:MAPT) View Subject | View Object

The Cdc37/Hsp90 inhibitors, Celasterol and Withaferin A (Zhang et al., 2008; Yu et al., 2010), reduce tau levels and a new compound, platycodin D has just been discovered (Li et al., 2017). Platycodin D does not affect the ATPase activity of Hsp90, but instead disrupts the interaction between Hsp90 and Cdc37 leading to client protein degradation without an increase in Hsp70 (Li et al., 2017). PubMed:29311797

a(PUBCHEM:14719853) decreases p(HGNC:MAPT) View Subject | View Object

Another N-terminal Hsp90 ATPase inhibitor, 17- AAG, was shown to decrease levels of phosphorylated tau in cells, and a related N-terminal Hsp90 ATPase inhibitor, PU- DZ8, reduced soluble and insoluble tau in tauP301L mice (Luo et al., 2007). PubMed:29311797

p(HGNC:PTGES3) increases p(HGNC:MAPT) View Subject | View Object

Inhibition of p23 in an siRNA screen of Hsp90 co-chaperones showed that silencing p23 reduced both total and phospho-tau (Jinwal et al., 2012, 2013). PubMed:29311797

p(HGNC:STIP1) decreases p(HGNC:MAPT) View Subject | View Object

A previous study found that when Hop was depleted using siRNA, there was an accumulation of tau (Jinwal et al., 2013). PubMed:29311797

p(HGNC:S100A1) increases p(HGNC:MAPT) View Subject | View Object

This study found that reductions in S100A1 also led to massive reductions in both phospho- and total tau levels in cells (Jinwal et al., 2013). PubMed:29311797

bp(GO:"clathrin-dependent endocytosis") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171]. PubMed:26751493

bp(GO:macroautophagy) decreases p(HGNC:MAPT) View Subject | View Object

A quite different strategy is to target tau clearance—e.g., by rapamycin that induces macroautophagy [175], inhibitors of Hsp90 chaperone protein that binds to misfolded proteins or by immunotherapeutic approaches [176]. PubMed:26751493

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493

a(HBP:HBP00006) increases tloc(p(HGNC:MAPT), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:Neurons)) View Subject | View Object

Importantly, neuronal uptake of HMW tau occurred in vivo as well; human tau uptake in neurons was detected in young rTg4510 (pre-tangle stage) (Fig. 1j–l) and WT (Supplementary Fig. 6) mice injected with the HMW SEC fraction of Tg4510 (12 months) brain extract, but not in those injected with the LMW fractions. PubMed:26458742

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Phosphatase treatment dephosphorylated tau in rTg4510 brain extract (Fig. 7d) without changing HMW tau levels (Fig. 7e), resulting in a significant reduction of cellular uptake of tau (Fig. 7f). PubMed:26458742

p(HGNC:MAPT, loc(MESH:"Neurofibrillary Tangles")) positiveCorrelation p(HGNC:MAPT, loc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau. PubMed:26195256

p(HGNC:MAPT, loc(MESH:"Cerebrospinal Fluid")) positiveCorrelation p(HGNC:MAPT, loc(MESH:"Neurofibrillary Tangles")) View Subject | View Object

ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau. PubMed:26195256

act(p(MESH:Calpain)) decreases p(HGNC:MAPT) View Subject | View Object

Phosphorylation of tau by protein kinase A increases its resistance to degradation by calpain PubMed:26195256

act(p(MESH:Lysosomes)) decreases p(HGNC:MAPT) View Subject | View Object

Tau is mainly cleared through intracellular degrada- tion by lysosomes via the autophagy–lysosome pathway, and by proteasomes via the ubiquitin–proteasome pathway.202 PubMed:26195256

p(MESH:Ubiquitin) decreases p(HGNC:MAPT) View Subject | View Object

Tau is mainly cleared through intracellular degrada- tion by lysosomes via the autophagy–lysosome pathway, and by proteasomes via the ubiquitin–proteasome pathway.202 PubMed:26195256

bp(GO:"regulation of microtubule cytoskeleton organization") association p(HGNC:MAPT) View Subject | View Object

Tau’s primary role within neurons is thought to be the regulation and stabilization of microtubule dynamics [1,2] PubMed:22817713

a(CHEBI:"3',5'-cyclic AMP") increases deg(p(HGNC:MAPT)) View Subject | View Object

Impairment of 26S proteasome induced by tau can be prevented early in disease through activation of cAMP-PKA signaling, and raising the levels of cAMP with rolipram may enhance tau degradation (Myeku et al. 2016) PubMed:29626319

a(CHEBI:"alpha,alpha-trehalose") decreases p(HGNC:MAPT) View Subject | View Object

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319

a(CHEBI:"proteasome inhibitor") decreases p(HGNC:MAPT) View Subject | View Object

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319

a(CHEBI:rolipram) increases deg(p(HGNC:MAPT)) View Subject | View Object

Impairment of 26S proteasome induced by tau can be prevented early in disease through activation of cAMP-PKA signaling, and raising the levels of cAMP with rolipram may enhance tau degradation (Myeku et al. 2016) PubMed:29626319

a(HP:"glymphatic system") decreases p(HGNC:MAPT) View Subject | View Object

It has been reported that ISF tau can be eliminated by the glymphatic system and the function of this clearance mechanism may be impaired due to the loss of AQP4 after TBI, which ultimately accelerates tau accumulation (Iliff et al.2014) PubMed:29626319

a(MESH:Aminopeptidases) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

a(MESH:Thrombin) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

bp(GO:"proteasomal protein catabolic process") increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012) PubMed:29626319

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012) PubMed:29626319

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319

bp(GO:phagocytosis) decreases p(HGNC:MAPT) View Subject | View Object

There was direct evidence to show that microglial phagocytosis plays a pivotal role in clearance of tau in vitro and in vivo (Bolos et al. 2015) PubMed:29626319

p(FPLX:CAPN) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

p(FPLX:Caspase) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

p(HGNC:BAG3) increases deg(p(HGNC:MAPT)) View Subject | View Object

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319

p(HGNC:CTSD) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

p(HGNC:HTRA1) increases deg(p(HGNC:MAPT)) View Subject | View Object

Human brain tau can be degraded by the proteases, such as cathepsin-D, amino peptidases, human high temperature requirement serine protease A1 (HTRA1), thrombin, caspases, and calpains (Chesser et al. 2013; Kenessey et al. 1997) PubMed:29626319

p(HGNC:NPAS4) increases deg(p(HGNC:MAPT)) View Subject | View Object

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319

path(MESH:"Brain Injuries, Traumatic") increases p(HGNC:MAPT) View Subject | View Object

It has been reported that ISF tau can be eliminated by the glymphatic system and the function of this clearance mechanism may be impaired due to the loss of AQP4 after TBI, which ultimately accelerates tau accumulation (Iliff et al.2014) PubMed:29626319

a(MESH:"Transport Vesicles") association p(HGNC:MAPT) View Subject | View Object

Rab7a (Rodriguez et al., 2017) and Rab1a (Mohamed et al., 2017) have been recently implicated in tau release, further suggesting that tau release involves vesicle transport. PubMed:29238289

act(a(MESH:Exosomes)) association p(HGNC:MAPT) View Subject | View Object

Tau from the CSF (Saman et al., 2012) and blood of patients with AD (Fiandaca et al., 2015) is associated with exosomes PubMed:29238289

a(MESH:Microglia) increases p(HGNC:MAPT) View Subject | View Object

N2a cells over-expressing tau (Wang et al., 2017) and microglia also release tau in an exosome-dependent manner PubMed:29238289

act(a(MESH:Microtubules)) association p(HGNC:MAPT) View Subject | View Object

Tau is well-recognized for its role in assembling/stabilizing microtubules although tau single knockout mice do not show major phenotypic changes in neuronal microtubule stability because of a putative functional redundancy PubMed:29238289

act(a(MESH:Neurons)) increases p(HGNC:MAPT) View Subject | View Object

In addition, stimulating neuronal activity in either cultured neurons or in vivo also enhances tau release PubMed:29238289

act(a(MESH:Neurons)) increases p(HGNC:MAPT) View Subject | View Object

this observation suggests that the activity-dependent release of tau participates in a positive feedback loop on neuronal activity. PubMed:29238289

a(MESH:Neurons) causesNoChange p(HGNC:MAPT) View Subject | View Object

CSF tau in APP transgenic mice is increased in an age- dependent manner without a global neuronal loss PubMed:29238289

complex(p(HGNC:HSPA8), p(INTERPRO:"Chaperone DnaJ")) decreases p(HGNC:MAPT) View Subject | View Object

However, other studies show that the majority of extracellular tau is membrane-free (Chai et al., 2012; Karch et al., 2012) and not associated with extracellular vesicles such as exosomes or ectosomes (i.e., plasma-membrane originating vesicles act(MESH:Exosomes) cnc p(HGNC:MAPT) SET Evidence = PubMed:29238289

p(HBP:"Tau fibrils") increases tloc(p(HGNC:MAPT)) View Subject | View Object

Subsequent studies have shown that injecting tau fibrils into the brain also induces trans- neuronal propagation in vivo PubMed:29238289

p(HGNC:RAB1A) association p(HGNC:MAPT) View Subject | View Object

Rab7a (Rodriguez et al., 2017) and Rab1a (Mohamed et al., 2017) have been recently implicated in tau release, further suggesting that tau release involves vesicle transport. PubMed:29238289

p(HGNC:RAB7A) association p(HGNC:MAPT) View Subject | View Object

Rab7a (Rodriguez et al., 2017) and Rab1a (Mohamed et al., 2017) have been recently implicated in tau release, further suggesting that tau release involves vesicle transport. PubMed:29238289

p(HGNC:SNAP23) increases p(HGNC:MAPT) View Subject | View Object

However, other studies show that the majority of extracellular tau is membrane-free (Chai et al., 2012; Karch et al., 2012) and not associated with extracellular vesicles such as exosomes or ectosomes (i.e., plasma-membrane originating vesicles act(MESH:Exosomes) cnc p(HGNC:MAPT) SET Evidence = PubMed:29238289

complex(GO:microtubule) association p(HGNC:MAPT) View Subject | View Object

The resulting MAP-decorated neurofilaments formed a viscous complex with microtubules, showing that some component of the MAPs mediated the association between the two filamentous organelles. PubMed:6543144

p(MESH:"SNARE Proteins") increases p(HGNC:MAPT) View Subject | View Object

However, other studies show that the majority of extracellular tau is membrane-free (Chai et al., 2012; Karch et al., 2012) and not associated with extracellular vesicles such as exosomes or ectosomes (i.e., plasma-membrane originating vesicles act(MESH:Exosomes) cnc p(HGNC:MAPT) SET Evidence = PubMed:29238289

a(CHEBI:"double-stranded DNA") association p(HGNC:MAPT) View Subject | View Object

In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wildtype and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. PubMed:21131359

bp(GO:myelination) association p(HGNC:MAPT) View Subject | View Object

Here we demonstrate that the Tau-Fyn interaction has a role in developmental myelination. CG-4 cells were stably transfected with control and experimental truncated Tau and transplanted in the brain and spinal cord of the md rats. In the brain, experimental cells have a severe defect in their ability to extend cellular processes and form myelin; in the spinal cord the cells extend cellular processes but the extent of myelination rostral and caudal to the injection site was decreased compared to control. Cultured experimental cells display shorter cellular process length. In addition experimental cells have Fyn largely in the cell body, whereas control cells distribute Fyn both in the cell body and the processes. Taken together these results demonstrate a direct effect of Tau in OLGs in in vivo myelination. PubMed:18680553

Annotations
Cell Ontology (CL)
oligodendrocyte

bp(MESH:"Hot Temperature") increases tloc(p(HGNC:MAPT), fromLoc(GO:cytoplasm), toLoc(GO:nucleus)) View Subject | View Object

In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wildtype and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. PubMed:21131359

bp(MESH:"Hot Temperature") negativeCorrelation p(HGNC:MAPT) View Subject | View Object

In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wildtype and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. PubMed:21131359

bp(MESH:"Oxidative Stress") increases tloc(p(HGNC:MAPT), fromLoc(GO:cytoplasm), toLoc(GO:nucleus)) View Subject | View Object

In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wildtype and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. PubMed:21131359

complex(GO:"neuron projection") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Tau protein plays a role in the extension and maintenance of neuronal processes through a direct association with microtubules. It is found in the axonal microtubules of mature neurons (Binder et al ., 1985) and in the axonlike elongated neurite processes synthesized by differentiating neurons in culture. To address this issue, three different tau protein fragments were synthesized in vitro: (a) the tau protein repeat domain (residues 237 to 367); (b) the amino terminal half of tau protein (residues 1-237) ; and (c) the carboxy terminal nonrepeat domain of tau protein (residues 358 to 430). From these results, we conclude the repeat domain contributes most of the binding energy for microtubules. PubMed:1918161

complex(GO:"polysomal ribosome") association p(HGNC:MAPT) View Subject | View Object

This antibody binds only to tau and localizes along microtubules in axons, somata, dendrites, and astrocytes and on ribosomes (polysomes) without phosphatase pretreatment. PubMed:2446784

act(complex(GO:"proteasome complex")) increases deg(p(HGNC:MAPT)) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

complex(GO:axon) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Tau protein plays a role in the extension and maintenance of neuronal processes through a direct association with microtubules. It is found in the axonal microtubules of mature neurons (Binder et al ., 1985) and in the axonlike elongated neurite processes synthesized by differentiating neurons in culture. To address this issue, three different tau protein fragments were synthesized in vitro: (a) the tau protein repeat domain (residues 237 to 367); (b) the amino terminal half of tau protein (residues 1-237) ; and (c) the carboxy terminal nonrepeat domain of tau protein (residues 358 to 430). From these results, we conclude the repeat domain contributes most of the binding energy for microtubules. PubMed:1918161

complex(GO:microtubule) association p(HGNC:MAPT) View Subject | View Object

ABaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABaC and tau bind to different domains on MTs. PubMed:10464280

complex(GO:neurofilament) association p(HGNC:MAPT) View Subject | View Object

The resulting MAP-decorated neurofilaments formed a viscous complex with microtubules, showing that some component of the MAPs mediated the association between the two filamentous organelles. PubMed:6543144

complex(a(CHEBI:"calcium(2+)"), p(FPLX:CALM), p(HGNC:MAPT)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

These findings provide new insights into the regulation of microtubule assembly, since Ca2+/calmodulin inhibition of tubulin polymerization into microtubules could be mediated by the direct binding of calmodulin to tau, thus preventing the interaction of this latter protein with tubulin. PubMed:2123288

p(HGNC:ANXA2) association p(HGNC:MAPT) View Subject | View Object

The data suggest that tau’s membrane association causes retention of tau in the tip of neurites, which is compromised by the R406W mutation. Also, after BAPTA treatment, the difference in the retention of wt tau and R406W tau was abolished (Fig. 9 D), which again suggests that tau trapping is caused by an interaction with AnxA2 at the membrane. PubMed:21339331

p(HGNC:BAG1) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

p(HGNC:BAG1) decreases deg(p(HGNC:MAPT)) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

p(HGNC:CDC37) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Previous work showed that Hsp90 inhibition with 17-AAG reduced phospho-tau levels in vivo (16, 23). We speculated that Cdc37 might modulate Hsp90 inhibitor efficacy for phosphotau. M17 cells were transfected with Cdc37 siRNA and then treated with 1 μM 17-AAG for 24 h. Indeed, reducing Cdc37 synergized with Hsp90 inhibition to reduce tau levels more potently than either condition alone (Fig. 6A). PubMed:21367866

act(p(SFAM:"HSP90 Family")) negativeCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

Previous work showed that Hsp90 inhibition with 17-AAG reduced phospho-tau levels in vivo (16, 23). We speculated that Cdc37 might modulate Hsp90 inhibitor efficacy for phosphotau. M17 cells were transfected with Cdc37 siRNA and then treated with 1 μM 17-AAG for 24 h. Indeed, reducing Cdc37 synergized with Hsp90 inhibition to reduce tau levels more potently than either condition alone (Fig. 6A). PubMed:21367866

p(HGNC:FKBP5) increases p(HGNC:MAPT) View Subject | View Object

We found that FKBP51 indeed could interact with tau from both AD patients and control cases (Fig. 3D), further suggesting a functionally relevant relationship between FKBP51 and tau. We then investigated whether FKBP51 would preferentially interact with phosphorylated tau species. We increased the number of samples per group (4 for AD and 4 for normal) and again co-immunoprecipitated FKBP51. After gel electrophoresis, immunoblotting showed increased association of pS396 and pS199-S202 tau species with FKBP51 in AD tissue (Fig S1). Indeed, we found that FKBP51 over-expression increased phospho- and total tau levels (by 80%) in HeLa cells stably expressing normal human tau, while FKBP52 over-expression had no affect (Fig.4A). These experiments were repeated multiple times and Student t-test of these replicates demonstrated that FKBP51 significantly increased total tau levels (p= 0.0104). PubMed:20071522

p(HGNC:FYN) association p(HGNC:MAPT) View Subject | View Object

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

Annotations
Cell Ontology (CL)
neuron
Cell Ontology (CL)
oligodendrocyte

complex(p(HGNC:GRB2), p(HGNC:MAPT)) association p(HGNC:MAPT) View Subject | View Object

As shown in Fig. 2A, tau co-sedimented with SH3 domains of cSrc, PLCgamma1, the N-terminal SH3 domain of Grb2, and most effectively with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. PubMed:18467332

complex(p(HGNC:GSK3B), p(HGNC:MAPT)) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

GSK3Beta may directly bind to tau within a GSK3Beta-tau complex.To identify the GSK3Beta-binding region within tau, we constructed three tau deletion mutants: R-tau-(1–244) containing the N-terminal projection domain, R-tau-(245–369) containing the microtubule-binding region, and R-tau-(245–441) containing both the microtubule-binding region and the C-terminal tail. We evaluated the binding of these mutants and wild-type R-tau with GST-GSK3Beta by the GST pull-down assay. GSK3Beta bound to wild type (Fig. 5B) and R-tau-(1–244) (Fig. 5C) but not R-tau-(245–369) (Fig. 5D) and R-tau-(245–441) (Fig.5E). These data demonstrate that GSK3Beta binds to the Nterminal projection domain of tau. PubMed:11812770

p(HGNC:YWHAZ) association p(HGNC:MAPT) View Subject | View Object

These observations suggested that 14-3-3zeta may be bound to GSK3Beta and/or tau within brain microtubules and may be a component of tau phosphorylation complex.Therefore, 14-3-3 must be the central molecule that holds tau and GSK3Beta within the complex. Indeed, FLAG-tau co-immunoprecipitated with HA-GSK3Beta from cells overexpressing FLAG-tau and HA-GSK3Beta only when these cells also overexpressed Xpress-14-3-3zeta (Fig. 6A, lanes 8 and 9), indicating that GSK3Beta associates with tau only in the presence of 14-3-3zeta. As discussed above, 14-3-3zeta binds to tau (36) and GSK3Beta (Fig. 5) directly. Taken together, these observations indicated that 14-3-3zeta connects GSK3Beta to tau in vivo. PubMed:12551948

Annotations
Experimental Factor Ontology (EFO)
HEK293

p(HGNC:HSPB1) causesNoChange p(HGNC:MAPT) View Subject | View Object

Here we show that heat shock protein 27 (Hsp27) preferentially binds pathological hyperphosphorylated tau and paired helical filaments tau directly but not non-phosphorylated tau. The formation of this complex altered the conformation of pathological hyperphosphorylated tau and reduced its concentration by facilitating its degradation and dephosphorylation. PubMed:14963027

Annotations
Uberon
temporal cortex

p(HGNC:S100B) association p(HGNC:MAPT) View Subject | View Object

We here confirmed the interaction of SlOOb with tau through affinity chromatography and crosslinking and demonstrated that such an interaction also inhibited mode I phosphorylation by a Ca2+/CaM-dependent kinase. Increasing Ca2+c oncentration to the 100 μM range potentiated the SlOOb effect. Therefore, although Ca2+-independent interactions may occur between SlOOb and protein tau, it is the Ca2+ form of SlOOb that has significant affinity for protein tau. In any case, Znz+ and Ca2+ both appear to be capabble of inducing a conformation in SlOOb that promotes its binding to target proteinins, including tau. PubMed:2833519

complex(p(HGNC:MAPT, pmod(Ph, Thr, 231)), p(HGNC:PIN1, frag("5_39"))) increases act(p(HGNC:MAPT)) View Subject | View Object

To examine whether Pin1 affects the ability of pTau to bind microtubules, we generated pTau in vitro using purified Cdc2 (refs 17, 18), and determined its ability to bind Taxol-stabilized microtubules with or without Pin1. Although Cdc2 phosphorylation disrupted the ability of tau to bind microtubules; the binding was fully restored by preincubation with Pin1 (Fig. 5a). Furthermore, Pin1 was detected in the fraction of tau-bound microtubules (Fig. 5a). However, no Pin1 was detected in the microtubule fraction if pTau was not added (Fig. 5a), indicating that Pin1 does not bind microtubules directly. Thus, Pin1 binds pTau and restores its ability to bind microtubules. PubMed:10391244

p(HGNC:MAPT, pmod(Ph, Thr, 231)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

To examine whether Pin1 affects the ability of pTau to bind microtubules, we generated pTau in vitro using purified Cdc2 (refs 17, 18), and determined its ability to bind Taxol-stabilized microtubules with or without Pin1. Although Cdc2 phosphorylation disrupted the ability of tau to bind microtubules; the binding was fully restored by preincubation with Pin1 (Fig. 5a). Furthermore, Pin1 was detected in the fraction of tau-bound microtubules (Fig. 5a). However, no Pin1 was detected in the microtubule fraction if pTau was not added (Fig. 5a), indicating that Pin1 does not bind microtubules directly. Thus, Pin1 binds pTau and restores its ability to bind microtubules. PubMed:10391244

p(HGNC:GRB2, frag("1_57")) association p(HGNC:MAPT) View Subject | View Object

As shown in Fig. 2A, tau co-sedimented with SH3 domains of cSrc, PLCgamma1, the N-terminal SH3 domain of Grb2, and most effectively with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. PubMed:18467332

p(HGNC:MAPT, pmod(Ub)) increases deg(p(HGNC:MAPT)) View Subject | View Object

The ubiquitin-targeted protein was identified as tau in paired helical filaments, and the conjugation sites were localized to the microtubule-binding region. PubMed:8391280

p(HGNC:PIK3R1, frag("3_79")) association p(HGNC:MAPT) View Subject | View Object

As shown in Fig. 2A, tau co-sedimented with SH3 domains of cSrc, PLCgamma1, the N-terminal SH3 domain of Grb2, and most effectively with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. PubMed:18467332

p(HGNC:PLCG1, frag("790_851")) association p(HGNC:MAPT) View Subject | View Object

As shown in Fig. 2A, tau co-sedimented with SH3 domains of cSrc, PLCgamma1, the N-terminal SH3 domain of Grb2, and most effectively with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. PubMed:18467332

p(HGNC:SRC, frag("84_145")) association p(HGNC:MAPT) View Subject | View Object

As shown in Fig. 2A, tau co-sedimented with SH3 domains of cSrc, PLCgamma1, the N-terminal SH3 domain of Grb2, and most effectively with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. PubMed:18467332

a(CHEBI:"advanced glycation end-product") decreases act(p(HGNC:MAPT)) View Subject | View Object

Glycation by AGE (Advanced Glycation End products) decreases MT binding, promotes aggregation, activates RAGE PubMed:8063802

Appears in Networks:

a(CHEBI:glyceraldehyde) increases p(HGNC:MAPT) View Subject | View Object

Aβ 42 in the medium decreased in a GA dose-dependent manner (Fig. 3a). In contrast, GA significantly increased tau and its phosphorylated form, p-tauT181 (Fig. 3b,c) in the medium. In addition, VEGF (Fig. 3e) and TGF-β (Fig. 3f), which are also AD biomarkers, were increased when the concentration of GA added was greater than 0.7 mM. PubMed:26304819

Appears in Networks:

a(CHEBI:salsalate) decreases p(HGNC:MAPT) View Subject | View Object

The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. PubMed:26390242

Appears in Networks:

a(HBP:"Tau epitope, PHF1") decreases act(p(HGNC:MAPT)) View Subject | View Object

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Appears in Networks:

a(HBP:"Tau epitope, PHF1") positiveCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639

Appears in Networks:

bp(GO:"microtubule polymerization") positiveCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Appears in Networks:

p(HGNC:TGM2) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau. PubMed:10537045

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p(INTERPRO:"Triosephosphate isomerase", pmod(NO)) association p(HGNC:MAPT) View Subject | View Object

Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau PubMed:19251756

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composite(p(HGNC:MAPT, pmod(Ac, Lys, 163)), p(HGNC:MAPT, pmod(Ac, Lys, 280)), p(HGNC:MAPT, pmod(Ac, Lys, 281)), p(HGNC:MAPT, pmod(Ac, Lys, 369))) decreases act(p(HGNC:MAPT)) View Subject | View Object

We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo. PubMed:28855586

Appears in Networks:

p(HBP:"Tau epitope, AT8") negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Appears in Networks:

p(HBP:"Tau epitope, AT8") decreases act(p(HGNC:MAPT)) View Subject | View Object

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Appears in Networks:

p(HBP:"Tau epitope, CP13") decreases act(p(HGNC:MAPT)) View Subject | View Object

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Appears in Networks:

p(HGNC:DAPK1) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

DAPK1-mediated increase in tau protein expression and stability were accompanied by increased Pin1 Ser71 phosphorylation. PubMed:24853415

Appears in Networks:

p(HGNC:HDAC6) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 174)) decreases deg(p(HGNC:MAPT)) View Subject | View Object

The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. PubMed:26390242

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 18)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 197)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 29)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 394)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers. PubMed:16566606

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 163)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 174)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 180)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 190)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

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p(HGNC:MAPT, pmod(Me, Lys, 24)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 254)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 259)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 267)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 290)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 290)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Me, Lys, 353)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 44)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys, 67)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Me2, Lys, 311)) association p(HGNC:MAPT) View Subject | View Object

An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1). PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 214)) decreases act(p(HGNC:MAPT)) View Subject | View Object

>8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain PubMed:8226987

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p(HGNC:MAPT, pmod(Ph, Ser, 261)) decreases act(p(HGNC:MAPT)) View Subject | View Object

>8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain PubMed:8226987

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p(HGNC:MAPT, pmod(Ub)) positiveCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation. PubMed:25378699

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p(HGNC:MAPT, pmod(Ub)) negativeCorrelation act(p(HGNC:MAPT)) View Subject | View Object

We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding. PubMed:24905733

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p(HGNC:MAPT, pmod(Ub, Lys, 254)) association p(HGNC:MAPT) View Subject | View Object

However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254. PubMed:22033876

Appears in Networks:
Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:PIN1, pmod(Ac, Lys, 46)) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions. PubMed:22926167

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p(HGNC:PIN1, pmod(Ph, Ser, 16)) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions. PubMed:22926167

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p(HGNC:PIN1, pmod(Ph, Ser, 65)) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions. PubMed:22926167

Appears in Networks:

p(HGNC:PIN1, pmod(Ph, Ser, 71)) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

DAPK1-mediated increase in tau protein expression and stability were accompanied by increased Pin1 Ser71 phosphorylation. PubMed:24853415

Appears in Networks:

p(HGNC:PIN1, pmod(Ph, Ser, 71)) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions. PubMed:22926167

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act(p(HGNC:STUB1)) increases deg(p(HGNC:MAPT)) View Subject | View Object

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639

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p(MGI:Sirt3) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

After pretreating hTau neurons with oligo Aβ-42 (1000 ng/ml), Sirt3 levels were reduced (Fig. 6b and e). This reduction in Sirt3 was translated into an increase in total tau and Ac-tau. PubMed:29540553

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g(HGNC:APP, var("?")) increases p(HGNC:MAPT) View Subject | View Object

Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36 Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD. PubMed:30444369

p(FPLX:PPP2, pmod(Me)) regulates p(HGNC:MAPT) View Subject | View Object

In cultured cells, deregulation of PP2A methylation also affects APP processing (Sontag et al.,2007), neurite outgrowth (Sontag et al.,2010) and tau distribution (Sontag et al.,2013). PubMed:24653673

bp(GO:"axonal transport") association p(HGNC:MAPT) View Subject | View Object

Tau protein is a typical microtubule-associated protein (MAP) and thus is directly implicated in maintaining the integrity and stability of the micro- tubules and involved in axonal transport. On the other hand, recent findings propose a direct role for APP in axonal transport, as APP can link to kinesins moving along the microtubules (Kamal et al., 2001). PubMed:12428809

p(HGNC:OTUB1) regulates p(HGNC:MAPT) View Subject | View Object

Taken together, our data indicate that Otub1, a deubiquitinating enzyme, is a novel positive regulator of Tau aggregation and Tau stability in vitro, in a nonneuronal cell line. PubMed:28083634

p(HGNC:OTUB1) decreases deg(p(HGNC:MAPT)) View Subject | View Object

We found that Tau degradation was significantly impaired in primary neurons infected with Otub1 WT, but not with catalytically dead mutant C91A, compared with GFP control. PubMed:28083634

p(HGNC:OTUB1, var("p.Cys91Ala")) causesNoChange deg(p(HGNC:MAPT)) View Subject | View Object

We found that Tau degradation was significantly impaired in primary neurons infected with Otub1 WT, but not with catalytically dead mutant C91A, compared with GFP control. PubMed:28083634

a(CHEBI:"methylene blue") decreases p(HGNC:MAPT) View Subject | View Object

Methylene blue, a contrast agent that can reduce tau misfolding, has also been shown to induce macroautophagy, as indicated by elevated Beclin 1 and LC3-II levels and reduced tau and p62 levels in organotypic neuronal cultures and a mouse model of FTD [159] PubMed:29758300

a(CHEBI:sirolimus) decreases p(HGNC:MAPT) View Subject | View Object

Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53] PubMed:29758300

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Evidence suggests that CMA can degrade tau via the chaperone heat shock cognate of 70 kDa (Hsc70), which recognizes KFERQ-like motifs and transfers its substrates via LAMP-2 into the lysosome [47] PubMed:29758300

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

composite(p(HGNC:HSPA8), p(HGNC:LAMP2)) increases tloc(p(HGNC:MAPT), fromLoc(GO:cytosol), toLoc(GO:lysosome)) View Subject | View Object

Evidence suggests that CMA can degrade tau via the chaperone heat shock cognate of 70 kDa (Hsc70), which recognizes KFERQ-like motifs and transfers its substrates via LAMP-2 into the lysosome [47] PubMed:29758300

p(HGNC:HSPA8) increases deg(p(HGNC:MAPT)) View Subject | View Object

Evidence suggests that CMA can degrade tau via the chaperone heat shock cognate of 70 kDa (Hsc70), which recognizes KFERQ-like motifs and transfers its substrates via LAMP-2 into the lysosome [47] PubMed:29758300

p(HGNC:NBR1) association p(HGNC:MAPT) View Subject | View Object

NBR1 colocalizes with tau and has primary sequence domains for binding [52]. PubMed:29758300

p(HGNC:SQSTM1) increases deg(p(HGNC:MAPT)) View Subject | View Object

Evidence that p62 facilitates tau degradation has been demonstrated in several studies where p62 colocalized with tau in NFTs from AD patients [53]. PubMed:29758300

p(HGNC:TREM2) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

In a more recent GWAS investigation, TREM2 (triggering receptor expressed on myeloid cells 2) was identified as one of the markers strongly associated with increased levels of tau and phosphorylated tau in cerebrospinal fluid from AD patients [91]. PubMed:29758300

path(HBP:"mitochondrial dysfunction") increases p(HGNC:MAPT) View Subject | View Object

Previous studies demonstrate impaired mitochondrial function preceding the accumulation of hallmark proteins in AD, such as Aβ [123,124] and tau [125]. PubMed:29758300

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

path(MESH:"Frontotemporal Dementia") association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

path(MESH:"Niemann-Pick Diseases") association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

path(MESH:"Supranuclear Palsy, Progressive") association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

path(MESH:Tauopathies) association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

a(GO:"Lewy body") association p(HGNC:MAPT) View Subject | View Object

The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190

a(GO:"Pick body") association p(HGNC:MAPT) View Subject | View Object

The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein. PubMed:22908190

a(GO:lysosome) increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190

a(HBP:"paired helical filaments") association p(HGNC:MAPT) View Subject | View Object

This protein reactive with the initial anti-PHF sera was soon identified as tau, a microtubule-associated protein (MAP), based on its molecular weight, isoform change during development, microtubule- binding activity, and heat stability (Kosik et al. 1986; Nukina and Ihara 1986; see also Brion et al. 1985; Grundke-Iqbal et al. 1986; Wood et al. 1986; discovery of tau in PHF is reviewed in Mandelkow and Mandelkow 2011). PubMed:22908190

a(HBP:"paired helical filaments") association p(HGNC:MAPT) View Subject | View Object

Using well-characterized antibodies to various MAPs as well as PHF polyclonal antibodies, tau had recently been established as a major component of PHFs (see above and Mandelkow and Mandelkow 2011). PubMed:22908190

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Incomplete charperone-mediated autophagy of tau generates fragments that aggregate and are cleared by macroautophagy (Wang et al. 2009). PubMed:22908190

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005). PubMed:22908190

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

p(HBP:"20 S Proteasome") increases deg(p(HGNC:MAPT)) View Subject | View Object

As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005). PubMed:22908190

p(FPLX:CAPN) increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190

p(FPLX:Caspase) increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190

a(CHEBI:"(-)-anisomycin") decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Conversely, treatment with protein translation inhibitors, cycloheximide or anisomycin, alone (Fig. S8A and B) almost completely abrogated MAPT missorting (schematic in Fig. 2E). These results suggest that the dendritic MAPT is locally generated. PubMed:30145931

a(CHEBI:"alpha,alpha-trehalose") decreases p(HGNC:MAPT) View Subject | View Object

Our previous study [23] had shown that trehalose induces autophagy in primary neurons and in an N2a cell model of tauopathy, and efficiently reduces the level of MAPT and MAPT aggregation. PubMed:30145931

a(CHEBI:cycloheximide) decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Conversely, treatment with protein translation inhibitors, cycloheximide or anisomycin, alone (Fig. S8A and B) almost completely abrogated MAPT missorting (schematic in Fig. 2E). These results suggest that the dendritic MAPT is locally generated. PubMed:30145931

a(CHEBI:rolipram) decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Treatment with rolipram (10 µM) on the neuritic side for 24 h (Fig. 5C) supressed missorting of MAPT down to 4.5±0.4% dendrites, far below the control level (20.5±5.6% dendrites) (Fig. 5D), thereby confirming the role of the proteasome in degrading dendritic MAPT. PubMed:30145931

a(CHEBI:wortmannin) increases p(HGNC:MAPT) View Subject | View Object

Compared with the MAPT-free dendrites of control neurons (Fig. S4A, 1.8±0.1), a substantial increase of SQSTM1 level (21.1±0.9) was observed in MAPT-containing dendrites upon wortmannin treatment (Fig. S4B). PubMed:30145931

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931

bp(GO:aging) increases p(HGNC:MAPT) View Subject | View Object

At more mature ages (DIV14 - DIV21), MAPT localization is mainly found in the axons with only basal levels in the somatodendritic compartment, consistent with earlier findings [20]. PubMed:30145931

bp(GO:aging) decreases p(HGNC:MAPT) View Subject | View Object

At more mature ages (DIV14 - DIV21), MAPT localization is mainly found in the axons with only basal levels in the somatodendritic compartment, consistent with earlier findings [20]. PubMed:30145931

bp(GO:autophagy) decreases p(HGNC:MAPT) View Subject | View Object

In controls, the fraction of MAPT-containing dendrites on the neuritic side was low (~14%), but local treatment with inhibitors of either autophagy (wortmannin [Fig. 3B], bafilomycin A 1 [Fig. S3A]) or the proteasome (epoxomicin [Fig. 3C], lactacystin [Fig. S3B]) caused a pronounced 4-to 5-fold increase of MAPT-containing dendrites (to levels of ~50-76%) (Fig. 3D). PubMed:30145931