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p(HGNC:MAPT, pmod(Ph))

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Entity

Name
MAPT
Namespace
hgnc
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Appears in Networks 40

Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-b peptide and s levels: target engagement, tolerability and pharmacokinetics in humans v0.1.0

APP processing in Alzheimer's disease v1.0.1

APP processing in Alzheimer's disease

Proteolytic processing of Alzeimer's beta-amyloid precursor protein v1.0.1

Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. v1.0.0

Alzheimer's Disease: Targeting the Cholinergic System v1.0.0

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

Nuclear receptors as therapeutic targets for Alzheimer's disease. v1.0.0

Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications v1.0.0

Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5 v1.0.0

Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease v1.0.0

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

Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers v1.0.0

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. v1.0.0

Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. v1.0.0

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies v1.0.0

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

Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. v1.0.0

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

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

Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies v1.0.0

Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain v1.0.1

Clearance systems in the brain-implications for Alzheimer disease. v1.0.1

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport. v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease v1.0.0

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

Clearance of Amyloid Beta and Tau in Alzheimer’s Disease:from Mechanisms to Therapy v1.0.1

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

Inflammasome Involvement in Alzheimer’s Disease v1.0.0

Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer’s Disease v1.0.0

Chronic Anatabine Treatment Reduces Alzheimer ’ s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD v1.0.0

Assembly and structure of protein phosphatase 2A v1.0.0

Protein phosphatase 2A dysfunction in Alzheimer’s disease v1.0.0

Axonal Transport, Tau Protein, and Neurodegeneration in Alzheimer’s Disease v1.0.0

Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo v1.0.0

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity v1.0.0

Caenorhabditis elegans models of tauopathy v1.0.0

Tau in physiology and pathology v1.0.0

New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases v1.0.0

Upstream regulators and downstream effectors of NF-κBinAlzheimer's disease v1.0.0

In-Edges 201

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

Appears in Networks:

a(PUBCHEM:11249342) decreases p(HGNC:MAPT, pmod(Ph)) 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

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bp(GO:"neurofibrillary tangle assembly") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is also noteworthy that Abeta-induced tau protein phosphorylation in PC12 cells is inhibited not only by alpha7 agonists, as would be predicted from the role of alpha7 nAChRs in neuroprotection, but also by alpha-bungarotoxin (Hu et al., 2008), as might be predicted if the competition by alpha-bungarotoxin for the Abeta site blocked a direct action of Abeta on nAChRs. It is therefore possible that the toxicity of Abeta is mediated, at least in part, through a direct physical interaction between Abeta and nAChRs. PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

act(a(MESH:Bungarotoxins)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is also noteworthy that Abeta-induced tau protein phosphorylation in PC12 cells is inhibited not only by alpha7 agonists, as would be predicted from the role of alpha7 nAChRs in neuroprotection, but also by alpha-bungarotoxin (Hu et al., 2008), as might be predicted if the competition by alpha-bungarotoxin for the Abeta site blocked a direct action of Abeta on nAChRs. It is therefore possible that the toxicity of Abeta is mediated, at least in part, through a direct physical interaction between Abeta and nAChRs. PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is also noteworthy that Abeta-induced tau protein phosphorylation in PC12 cells is inhibited not only by alpha7 agonists, as would be predicted from the role of alpha7 nAChRs in neuroprotection, but also by alpha-bungarotoxin (Hu et al., 2008), as might be predicted if the competition by alpha-bungarotoxin for the Abeta site blocked a direct action of Abeta on nAChRs. It is therefore possible that the toxicity of Abeta is mediated, at least in part, through a direct physical interaction between Abeta and nAChRs. PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

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

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

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complex(p(HGNC:FYN), p(HGNC:MAPT)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

FYN physically interacts with and phosphorylates tau protein, and the affinity of this physical interaction is enhanced in AD-associated mutations in tau protein (Bhaskar et al., 2005). Abeta rapidly induces tyrosine phosphorylation of many proteins (including tau protein) in human and cultured rat cortical neurons (Williamson et al., 2002). This phosphorylation is concomitant with phosphorylation and inactivation of focal adhesion kinase 1 (FADK1, a major downstream target of FYN), is blocked by inhibitors of SRC kinases and PI3K, and involves FYN associating physically with FADK1 (Williamson et al., 2002). PubMed:19293145

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composite(p(FPLX:ERK), p(HGNC:CHRNA7)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In neuroblastoma cells, as well as cultured hippocampal neurons, Abeta activates JNK and ERK, and blocking these prevents Abeta hyperphosphorylating tau protein, as does alpha7 antisense oligonucleotides or alpha7 antagonists, suggesting that Abeta may trigger tau protein phosphorylation through ERK and JNK via alpha7 receptors (Wang et al., 2003b). Abeta leads to phosphorylation of AKT in cultured mouse neurons through a mechanism that requires alpha7 nAChRs (Abbott et al., 2008), AKT phosphorylation levels returning to baseline upon prolonged application of Abeta. PubMed:19293145

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composite(p(FPLX:JNK), p(HGNC:CHRNA7)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In neuroblastoma cells, as well as cultured hippocampal neurons, Abeta activates JNK and ERK, and blocking these prevents Abeta hyperphosphorylating tau protein, as does alpha7 antisense oligonucleotides or alpha7 antagonists, suggesting that Abeta may trigger tau protein phosphorylation through ERK and JNK via alpha7 receptors (Wang et al., 2003b). Abeta leads to phosphorylation of AKT in cultured mouse neurons through a mechanism that requires alpha7 nAChRs (Abbott et al., 2008), AKT phosphorylation levels returning to baseline upon prolonged application of Abeta. PubMed:19293145

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a(CHEBI:"amyloid-beta") regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

However, further studies have demonstrated that nicotinic receptor activation can lead to an increase in Aβ-mediated tau phosphorylation PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

act(a(MESH:"Receptors, Nicotinic")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

However, further studies have demonstrated that nicotinic receptor activation can lead to an increase in Aβ-mediated tau phosphorylation PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta PubMed:24590577

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a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Chronic treatment with AF267B reduces Abeta plaques and tau hyperphosphorylation and rescues learning and memory impairments in 3×Tg AD mice PubMed:24590577

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Annotations
MeSH
Alzheimer Disease

act(p(HGNC:CHRM1)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta PubMed:24590577

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Annotations
Experimental Factor Ontology (EFO)
PC12

p(HGNC:PPP2CA) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau PubMed:26631930

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a(CHEBI:"all-trans-retinoic acid") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77]. PubMed:21718217

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Annotations
Confidence
Medium

p(GFAM:"Protein phosphatase catalytic subunits") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In addition, subunits of protein phosphatase PP1 (Unigene-NCBI annotation PPP1CA and PPP1CC) mRNAs were downregulated in CBF neurons in AD [135]. This observation is interesting in light of the observation that PP1 can phosphorylate tau on several serine/threonine residues and experimental downregulation of PP1 activity leads to increased tau hyperphosphorylation [137,138], which may affect NFT formation in CBF neurons. PubMed:18986241

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Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

complex(a(HBP:HBP00172), p(HGNC:CDK5)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

We find that this kinase shows good activity towards tau only when complexed with another protein of Mr 25 kDa, presumably a regulatory subunit analogous to one of the cyclins PubMed:8282104

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Confidence
High

p(HGNC:CDK5) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In conclusion, this cdc2-like kinase activity towards tau occurs in brain tissue and has an Mr of 31 kDa. These features are suggestive of other cdc2-like kinases cloned recently from brain, termed nclk [ 141, PSSARLE [28], or cdk5 [42,49]. Indeed, the 31 kDa protein reacted with an antibody specific for cdk5. Thus, the kinase isolated here is very similar if not identical to cdk5. PubMed:8282104

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Annotations
Confidence
High
MeSH
Brain

p(FPLX:ERK) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The Mr shifts up with time in several stages, very similar to our earlier observations with the brain kinase activity, MAP kinase and GSK3 (Fig. 2,) PubMed:8282104

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Annotations
Confidence
High

p(FPLX:GSK3) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The Mr shifts up with time in several stages, very similar to our earlier observations with the brain kinase activity, MAP kinase and GSK3 (Fig. 2,) PubMed:8282104

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Annotations
Confidence
High

p(HGNC:CDK2) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The Mr shifts up with time in several stages, very similar to our earlier observations with the brain kinase activity, MAP kinase and GSK3 (Fig. 2,) PubMed:8282104

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Annotations
Confidence
High

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

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Annotations
Confidence
High
MeSH
Neurons

rxn(reactants(p(HGNC:MAPT)), products(p(HGNC:MAPT, pmod(Ph)))) hasProduct p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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bp(MESH:Autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) 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

Appears in Networks:
Annotations
MeSH
Hippocampus
Text Location
Review

bp(MESH:Autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) 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

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Annotations
MeSH
Hippocampus
Text Location
Review

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

In CHO cells overexpressing P301L mutant tau, treatment with the Hsp90 inhibitor geldanamycin led to a more pronounced proteasome-mediated reduction in tau phosphorylated at proline-directed S/T sites compared to total tau (67). PubMed:24027553

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Text Location
Review

path(MESH:"Alzheimer Disease") regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

A final point of interest relates to potential upstream modifications of tau. Endogenous tau is phosphorylated, and in AD, tau phosphorylation becomes dysregulated. This may interfere with subsequent processes including cleavage and degradation. For example, tau that is in the cis-conformation at T231 appears resistant to degradation, as cis-tau is found in dystrophic neurites while trans-tau is not. Additionally cis-tau partitions to the insoluble fraction (30). Phosphorylation at T231 prevents the isomerase Pin1 from converting cis-tau to trans-tau (30). PubMed:24027553

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Text Location
Review

path(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The predominant post-translational modification of tau in the NFTs is phosphorylation; however numerous modifications have been noted including truncation, acetylation, nitration, and several others (2–4). PubMed:24027553

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Text Location
Review

a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

While vehicle treated cells (Fig. 2A and B) exhibited low phosphotau immunofluorescence, cells treated with 1 microM biotinylated ADDLs (bADDLs) for 6 h (Fig. 2C and D) showed a significant increase in P-tau immunofluorescence (Fig. 2D). PubMed:17403556

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Text Location
Results

a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Hippocampal neurons exposed to Abeta fibrils rather than oligomers also showed elevated P-tau immunofluorescence (Fig. 2N–P) However, although fibrils could be seen attached to neurons, they did not bind in the synaptic pattern observed for ADDLs (Fig. 2O and P). PubMed:17403556

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Text Location
Results

path(HBP:Neurodegeneration) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

We note that these observed increases in tau phosphorylation occurred well before neuronal death (Fig. 1B), consistent with this pathology representing an early stage in neurodegeneration. PubMed:17403556

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Text Location
Results

a(HBP:"amyloid-beta oligomers") regulates p(HGNC:MAPT, pmod(Ph)) 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

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Annotations
MeSH
Post-Synaptic Density
Text Location
Results

act(p(HGNC:MAPT)) association p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:
Annotations
MeSH
Post-Synaptic Density
Text Location
Results

p(HBP:"AT8 tau", pmod(Ph)) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Soluble AT8 tau monomers inhibited anterograde FAT (Fig. 6 A, C), while retrograde trans- port was unaffected (Fig. 6 A, D). These data indicate that phos- phorylation of tau at the AT8 epitope, which is associated with hyperphosphorylation of tau in AD and other tauopathies, renders soluble monomeric tau capable of inhibiting antero- grade FAT. PubMed:21734277

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a(CHEBI:"methylene blue") decreases p(HGNC:MAPT, pmod(Ph)) 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

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

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

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p(FPLX:HSP90) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945

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p(FPLX:HSP90) regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau PubMed:21882945

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p(HGNC:BAG2) association deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

However, another related BAG family member, BAG2, interacts with Hsp70 and tau but, unlike BAG1, assists clearance of phosphorylated tau [132] PubMed:21882945

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complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) hasComponent p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Hsp27 has emerged as a potential target for tau regulation based on early findings that it preferentially binds to phosphorylated and hyperphosphorylated tau and promotes their clearance [125,126] PubMed:21882945

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act(p(HGNC:CDK5)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

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act(p(HGNC:GSK3B)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

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p(HGNC:HSPH1) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

This co-chaperone is of interest in tauopathies because Hsp110 knockout mice show an age-dependent accumulation of phosphorylated tau in the hippocampus [135]. PubMed:21882945

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Annotations
MeSH
Hippocampus

act(p(HGNC:MARK2)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

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act(p(HGNC:MARK2)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events. PubMed:21882945

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p(HGNC:PPP2R5B) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding PubMed:21882945

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p(HGNC:PPP5C) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding PubMed:21882945

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a(HBP:"Tau antibody, 40E8") decreases p(HGNC:MAPT, pmod(Ph)) 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

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MeSH
Alzheimer Disease
Text Location
Results

a(HBP:"Tau antibody, pS396") decreases p(HGNC:MAPT, pmod(Ph)) 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

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Annotations
MeSH
Alzheimer Disease
Text Location
Results

a(CHEBI:"amyloid-beta polypeptide 42") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Compared with control neurons, the effects of Ab42 on tau phosphorylation at CP13, PHF-1 and AT180 epitopes were significantly ameliorated in AK1 knockdown cortical neurons PubMed:22419736

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

Soluble oligomers of Ab42 serve as the prominent synapto- toxic form and induce tau hyperphosphorylation PubMed:22419736

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act(p(ECCODE:"2.7.11.31")) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

These results indicate that AMPK activity is impaired by Ab42 in the neuronal cells in which tau phosphor- ylation increased. PubMed:22419736

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p(HGNC:AK1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The data suggest that the increased expres- sion of AK1 can enhance tau aggregation as well as tau phos- phorylation. PubMed:22419736

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path(MESH:"Retinal Degeneration") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

These results indicate that AK1 exacerbates rough eye phenotype and tau hyperpho- sphorylation in a tauopathy model organism and that there is a close correlation between the exacerbated rough eye pheno- type and tau phosphorylation. PubMed:22419736

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a(CHEBI:tanespimycin) decreases p(HGNC:MAPT, pmod(Ph)) 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

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p(HGNC:PTGES3) increases p(HGNC:MAPT, pmod(Ph)) 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

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act(p(HGNC:PPP5C)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004). PubMed:29311797

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MeSH
Cerebral Cortex

p(HGNC:S100A1) increases p(HGNC:MAPT, pmod(Ph)) 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

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act(p(HGNC:GSK3B), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Cdc37 is also required for the stable folding of protein kinases in coordination with Hsp90 (Calderwood, 2015). Many of these kinases are known to phosphorylate tau at sites associated with AD, such as GSK3β and MAPK13 (Taipale et al., 2012; Jin et al., 2016). PubMed:29311797

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MeSH
Cerebral Cortex

act(p(HGNC:MAPK13), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Cdc37 is also required for the stable folding of protein kinases in coordination with Hsp90 (Calderwood, 2015). Many of these kinases are known to phosphorylate tau at sites associated with AD, such as GSK3β and MAPK13 (Taipale et al., 2012; Jin et al., 2016). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

In tauopathic mice, CHIP regulates the removal of tau species that have undergone abnormal phosphorylation and folding (Dickey et al., 2007b). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

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

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004). PubMed:29311797

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MeSH
Cerebral Cortex

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

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

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Annotations
Confidence
High
MeSH
Brain

p(MESH:"Cyclic AMP-Dependent Protein Kinases") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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

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MeSH
Choroid Plexus

path(MESH:Inflammation) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Inflammation, a common feature of AD, can affect ligand affinity by making the pH more acidic, which promotes hyperphosphorylation of tau and induces conforma- tional changes in Aβ that hinder its clearance. PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

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

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

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

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3] PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

a(CHEBI:"(-)-epigallocatechin 3-gallate") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Epigallocatechin-3-gallate enhances the clearance of ADrelevant phosphorylated tau species via increasing mRNA expression of autophagy adaptor proteins NDP52 and p62 (Chesser et al. 2016) PubMed:29626319

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a(CHEBI:Temsirolimus) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

Appears in Networks:

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

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

Appears in Networks:

a(CHEBI:wogonin) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

Appears in Networks:

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) 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

Appears in Networks:

p(HGNC:NPAS4) increases deg(p(HGNC:MAPT, pmod(Ph))) 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

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p(HGNC:TFEB) regulates deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

For example, like Aβ, clearance of pTau/NFT also can be regulated by TFEB, which increases the activity of autophagy and lysosome (Polito et al. 2014) PubMed:29626319

Appears in Networks:

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

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
Disease Ontology (DO)
Down syndrome

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

In PSP cases, both coiled bodies (Fig. 2 D-F) and NFTs (Fig. 2G-I) in the striatum showed a complete co-localisation of PICALM and phosphotau immunoreactivies. PubMed:27260836

Appears in Networks:
Annotations
Uberon
striatum
Disease Ontology (DO)
progressive supranuclear palsy

p(HGNC:BAG1) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

p(SFAM:"HSP90 Family") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

To test the effect of Hsp90 on tau phosphorylation, this protein was mixed with tau protein in the presence of GSK-3 and ATP. Figure 4 shows that tau phosphorylation increases in the presence of increased added amounts of Hsp90. PubMed:19363271

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p(HGNC:FYN) increases p(HGNC:MAPT, pmod(Ph)) 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

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Cell Ontology (CL)
neuron

p(HGNC:HSPB1) decreases act(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Taken together, pathological hyperphosphorylated tau caused cell death, and Hsp27 attenuated the cell toxicity of pathological hyperphosphorylated tau. PubMed:14963027

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Annotations
Uberon
temporal cortex

act(p(HGNC:GSK3B)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In cells that were co-transfected with fixed amounts of FLAG-tau and HA-GSK3Beta but different amounts of Xpress-14-3-3zeta, FLAG-tau phosphorylation increased progressively with the increase in the amount of Xpress-14-3-3zeta (lanes 7–9). This increase was evident not only by an increased immunoreactivity against all tau phosphorylation-sensitive antibodies tested but also by a retarded mobility of FLAG-tau on the SDS gel, a characteristic feature of hyperphosphorylated tau (2, 3). Thus, 14-3-3zeta profoundly stimulated GSK3Beta-catalyzed tau phosphorylation in vivo. PubMed:12551948

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Annotations
Experimental Factor Ontology (EFO)
HEK293

complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) increases deg(p(HGNC:MAPT, pmod(Ph))) 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

Appears in Networks:
Annotations
Uberon
temporal cortex

p(HGNC:HSPB1) association p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:
Annotations
Uberon
temporal cortex

complex(p(HGNC:MAPT, pmod(Ph)), p(HGNC:STUB1), p(HGNC:UBE2D2)) hasComponent p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202)) isA p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 396)) isA p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 404)) isA p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 205)) isA p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

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

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

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act(p(SFAM:"CAMK2 Family")) increases p(HGNC:MAPT, pmod(Ph)) 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

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rxn(reactants(p(HGNC:MAPT, pmod(Ph))), products(a(CHEBI:"phosphate(3-)"), p(HGNC:MAPT))) hasReactant p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

rxn(reactants(p(HGNC:MAPT, pmod(Ph))), products(a(CHEBI:"phosphate(3-)"), p(HGNC:MAPT))) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Thus, MTs inhibited the rate of tau dephosphorylation by ABaC. PubMed:10464280

Appears in Networks:

a(CHEBI:"advanced glycation end-product") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Recently, Li et al. (2012b) have demonstrated in their study that AGEs can induce tau hyperphosphorylation through receptor for advanced glycation end product (RAGE)-mediated glycogen synthase kinase 3 (GSK-3) activation and targeting RAGE/GSK-3 pathway can improve AD-like changes. PubMed:24183963

Appears in Networks:

a(CHEBI:"dimethyl fumarate") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively. PubMed:29121589

Appears in Networks:

a(CHEBI:alsterpaullone) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. PubMed:10998059

Appears in Networks:

complex(GO:"tubulin complex") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Taken together, these results indicate that the binding of P-Tau to microtubules suppresses its dephosphorylation. PubMed:19401603

Appears in Networks:

complex(p(FPLX:PPP2), p(HGNC:MAPT)) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo PubMed:23943618

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

complex(p(HGNC:MAPT, pmod(Ph)), p(HGNC:SMAD2)) hasComponent p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

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 p(HGNC:MAPT, pmod(Ph)) 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(HGNC:CSNK1D) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau-phosphorylation properties dependent on co-factors (Km 8 to 15 uM, Vmax 0.8 to 4 uM/min/mg protein) and Km for ATP is 2uM PubMed:18239272

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Recently, Li et al. (2012b) have demonstrated in their study that AGEs can induce tau hyperphosphorylation through receptor for advanced glycation end product (RAGE)-mediated glycogen synthase kinase 3 (GSK-3) activation and targeting RAGE/GSK-3 pathway can improve AD-like changes. PubMed:24183963

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. PubMed:18494933

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively. PubMed:29121589

Appears in Networks:

act(p(HGNC:GSK3B), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. PubMed:10998059

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied. PubMed:16630055

Appears in Networks:

p(HGNC:MAPT, pmod(Sumo, Lys, 340)) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:

act(p(HGNC:PPP2CA)) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Here we show that resveratrol treatment directly interferes with the MID1-α4-PP2A degradation complex by reducing MID1 protein expression in vitro and in vivo. This leads to an increase of microtubule-associated PP2A activity and a time- and dose-dependent dephosphorylation of Tau. Interestingly, we further show that MID1 expression is elevated in AD tissue. PubMed:29062069

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p(HGNC:S100B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. PubMed:18494933

Appears in Networks:

a(CHEBI:"nitric oxide") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Additionally, it can induce phosphorylation of the tau protein and promote for- mation of neurofibrillary tangles through the mitogen activated protein kinases-p38 (MAPK-p38) stress pathway [22, 54]. PubMed:27314526

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Annotations
Confidence
High
MeSH
Alzheimer Disease
NeuroMMSigDB
MAPK-JNK subgraph
NeuroMMSigDB
Nitric oxide subgraph
NeuroMMSigDB
Tau protein subgraph

p(HGNC:CDK5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Pro-inflammatory IL-18 increases AD-associated A beta deposition in human neuron-like cells in culture [55]. IL-18 also increases the expression of glycogen synthase kinase 3 beta (GSK-3 beta ) and cyclin-dependent kinase 5, both of which are involved in hyperphos- phorylation of the tau protein [56]. PubMed:27314526

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Cyclin-CDK subgraph
NeuroMMSigDB
GSK3 subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tau protein subgraph

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Pro-inflammatory IL-18 increases AD-associated A beta deposition in human neuron-like cells in culture [55]. IL-18 also increases the expression of glycogen synthase kinase 3 beta (GSK-3 beta ) and cyclin-dependent kinase 5, both of which are involved in hyperphos- phorylation of the tau protein [56]. PubMed:27314526

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Cyclin-CDK subgraph
NeuroMMSigDB
GSK3 subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tau protein subgraph

p(HGNC:CSNK1A1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Isoforms of CK1 are responsible for tau phosphorylation. 129 The enzyme can modulate the activity of γ-secretase and consequently the production of Aβ. PubMed:30444369

Appears in Networks:
Annotations
MeSH
Neurons

act(p(HGNC:GSK3B)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Moreover, estradiol has been shown to inhibit tau hyperphosphorylation and can also modulate glycogen synthase kinase-3β (GSK-3β) activity, a kinase that is involved in tau phosphorylation. Estradiol deactivates GSK-3β by inducing its phosphorylation, thereafter reducing tau phosphorylation. PubMed:30444369

Appears in Networks:

a(CHEBI:Anatabine) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. PubMed:26010758

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Annotations
MeSH
Tauopathies

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The specificity in this in vitro system is quite robust, as evidenced by the observation that the PP2A core enzyme exhibited a lower activity to dephosphorylate the Tau protein than the PP2A holoenzyme involving the B subunit, but a higher activity than the holoenzyme involving the B′ subunit PubMed:19277525

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The specificity in this in vitro system is quite robust, as evidenced by the observation that the PP2A core enzyme exhibited a lower activity to dephosphorylate the Tau protein than the PP2A holoenzyme involving the B subunit, but a higher activity than the holoenzyme involving the B′ subunit PubMed:19277525

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A, regulatory B subunit, B56")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The specificity in this in vitro system is quite robust, as evidenced by the observation that the PP2A core enzyme exhibited a lower activity to dephosphorylate the Tau protein than the PP2A holoenzyme involving the B subunit, but a higher activity than the holoenzyme involving the B′ subunit PubMed:19277525

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In vivo use of phosphatase inhibitors such as okadaic acid has been shown in many studies to induce cognitive impairment and widespread neurotoxic effects that are reminiscent of the hallmark pathological processes occurring in AD pathology, i.e., the accumulation of P-tau, amyloidogenesis, synapse loss and neurodegeneration (Malchiodi-Albedi et al., 1997; Arendt et al., 1998; Sun et al.,2003; Kamat et al.,2013) PubMed:24653673

Appears in Networks:

a(CHEBI:folates) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

a(CHEBI:homocysteine) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

bp(GO:"one-carbon metabolic process") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Remarkably, impairment of one-carbon metabolism in animal models can reproduce AD-like pathological features: accumulation of P-tau (Sontag et al.,2007; Zhang et al.,2008; Wei et al.,2011); enhanced amyloidogenesis (Pacheco-Quinto et al.,2006; Zhang et al.,2009; Zhuo et al.,2010; Zhuo and Pratico,2010); increased phosphorylation of APP at the regulatory Thr-668 site (Sontag et al.,2007; Zhang et al.,2009); increased sensitivity to amyloid toxicity (Kruman et al.,2002); and cognitive impairment (Bernardo et al.,2007; Wei et al.,2011; Rhodehouse et al., 2013). PubMed:24653673

Appears in Networks:

complex(GO:"protein phosphatase type 2A complex") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For instance, the Bα subunit specifically and markedly facilitates dephosphory- lation of tau by PP2A (Sontag et al.,1996; Xu et al.,2008). PubMed:24653673

Appears in Networks:

act(complex(GO:"protein phosphatase type 2A complex")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Besides Ser/Thr kinases, the protein tyrosine kinase src promotes the phosphorylation of PP2A on Tyr-307, resulting in PP2A inactivation and subsequent tau phosphorylation (Xiong et al.,2013; Arif et al.,2014). PubMed:24653673

Appears in Networks:

act(complex(GO:"protein phosphatase type 2A complex")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008). PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CA) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice PubMed:24653673

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is noteworthy that PP2A/Bα can directly bind to tau via a domain encompassing the microtubule-binding of tau; this interaction maximizes the efficiency of tau dephosphorylation by PP2A (Sontag et al.,1999; Xu et al.,2008; Figure 3A). PubMed:24653673

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For instance, the Bα subunit specifically and markedly facilitates dephosphory- lation of tau by PP2A (Sontag et al.,1996; Xu et al.,2008). PubMed:24653673

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is noteworthy that PP2A/Bα can directly bind to tau via a domain encompassing the microtubule-binding of tau; this interaction maximizes the efficiency of tau dephosphorylation by PP2A (Sontag et al.,1999; Xu et al.,2008; Figure 3A). PubMed:24653673

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008). PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008). PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673

Appears in Networks:

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

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

p(FPLX:PPP2, pmod(Me, Tyr, 307)) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Lastly, increased phosphorylation of PP2A at Tyr-307 has been found in P-tau-rich, tangle-bearing neurons from post-mortem brain (Liu et al.,2008b). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

p(HGNC:PPP2CA, var("p.Leu309Ala")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB, var("p.Leu309Ala")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice PubMed:24653673

Appears in Networks:

p(HGNC:PPP2R5D) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice PubMed:24653673

Appears in Networks:

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

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Vitamin B Deficiency") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

p(FPLX:CK2) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

Appears in Networks:

p(FPLX:ERK) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Appears in Networks:

p(FPLX:PKA) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

Appears in Networks:

p(FPLX:PPP1) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau protein is rapidly dephosphorylated by endogenous phosphatases such as protein phosphatases 1, 2A, and 2B (cal- cineurin) that are all present in the brain, and effec- tively dephosphorylate tau protein in vitro. PubMed:12428809

Appears in Networks:

p(FPLX:PPP2) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau protein is rapidly dephosphorylated by endogenous phosphatases such as protein phosphatases 1, 2A, and 2B (cal- cineurin) that are all present in the brain, and effec- tively dephosphorylate tau protein in vitro. PubMed:12428809

Appears in Networks:

p(FPLX:PPP3) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau protein is rapidly dephosphorylated by endogenous phosphatases such as protein phosphatases 1, 2A, and 2B (cal- cineurin) that are all present in the brain, and effec- tively dephosphorylate tau protein in vitro. PubMed:12428809

Appears in Networks:

p(HGNC:CAMK2B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

Appears in Networks:

p(HGNC:CDK1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Appears in Networks:

p(HGNC:CDK5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Appears in Networks:

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Appears in Networks:

p(HGNC:MAPK9) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Appears in Networks:

p(HGNC:MARK1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:OTUB1)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Since Otub1 interacts with Tau and promotes phosphorylated and aggregated Tau levels in primary neurons, we hypothesized that Otub1 could act as a Tau deubiquitinase, interfering with pathological Tau degradation and hence Tau aggregation. PubMed:28083634

Appears in Networks:

bp(GO:autophagy) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

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

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

complex(GO:"proteasome complex") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

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

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, var("p.Ala152Thr")) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers. PubMed:29758300

Appears in Networks:

p(FPLX:MAPK) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases. PubMed:29758300

Appears in Networks:

p(HGNC:CDK5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases. PubMed:29758300

Appears in Networks:

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases. PubMed:29758300

Appears in Networks:

p(HGNC:MTOR) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:

p(HGNC:TREM2) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) 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

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:MAPT, var("p.Lys280del")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Overall, Tau, both in the soluble and in the insoluble fractions, was phosphorylated to a higher degree in the pro-aggregant strain compared with the other two strains. PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Nonetheless, it is assumed that tau aggregation may be driven by phosphorylation at certain sites (95), whereas phosphorylation at other sites may inhibit aggregation (96). PubMed:29191965

Appears in Networks:

p(HGNC:CDK5) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Appears in Networks:

composite(p(HBP:"Tau isoform E (412 aa)", var("p.Val337Met")), p(HGNC:DDC)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Loss of bas-1 function improved the motor function, reduced insoluble tau and its phosphorylation and ameliorated the tau-induced neurodegeneration without increasing the longevity in TauV337M worms PubMed:29191965

Appears in Networks:

p(HGNC:PPM1A) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau PubMed:26631930

Appears in Networks:

p(FPLX:MAPK) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Appears in Networks:

p(FPLX:PKA) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Appears in Networks:

p(HGNC:GSK3B) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Appears in Networks:

p(HGNC:PPP1R8) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau PubMed:26631930

Appears in Networks:

p(HGNC:PPP1R8) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dephosphorylation of tau is achieved mainly by protein phosphatase (PP)2A, PP2B (calcineurin), and PP-1 (92). PubMed:29191965

Appears in Networks:

p(HGNC:PPP2CA) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dephosphorylation of tau is achieved mainly by protein phosphatase (PP)2A, PP2B (calcineurin), and PP-1 (92). PubMed:29191965

Appears in Networks:

p(HGNC:PPP3CB) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Dephosphorylation of tau is achieved mainly by protein phosphatase (PP)2A, PP2B (calcineurin), and PP-1 (92). PubMed:29191965

Appears in Networks:

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

Phosphorylation is generally increased in AD and can be recognized by diagnostic antibodies against phosphoepitopes PubMed:29191965

Appears in Networks:

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

For example, AD brain tau is;4-fold more phosphorylated than normal adult brain tau(93), but a high state of phosphorylation can also occur physiologically (e.g., in fetal brain or in hibernating animals (94). PubMed:29191965

Appears in Networks:

p(FPLX:PKA) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others PubMed:26631930

Appears in Networks:

p(HGNC:CAMK2A) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 259)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 290)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 321)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 353)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(NGlyco)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Furthermore, N‑glycosylation may facilitate tau hyperphosphorylation, as it suppresses the dephosphorylation and accelerates the phosphorylation of tau, probably because it changes the conformation of tau PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(OGlyco)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In contrast to N‑glycosylation, O‑GlcNAcylation (a type of O‑glycosylation) of tau may protect it against phosphorylation, as it occupies the Ser or Thr residue of Ser‑Pro or Thr-Pro motifs PubMed:26631930

Appears in Networks:

p(HGNC:MARK1) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others PubMed:26631930

Appears in Networks:

p(HGNC:PPP2CA) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Among them, PP2A is the main phosphatase:it accounts for ~70% of the human brain tau phosphatase activity, and its activity is reduced in the AD brain (by ~20% and ~40% in the grey and white matter, respectively) PubMed:26631930

Appears in Networks:

p(HGNC:PPP3CB) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau PubMed:26631930

Appears in Networks:

p(HGNC:PPP5C) directlyDecreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Protein phosphatase 1 (PP1), PP2A, PP2B, PP2C and PP5 have all been implicated in the dephosphorylation of tau PubMed:26631930

Appears in Networks:

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

In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule. PubMed:26631930

Appears in Networks:

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

This view is supported by a recent study showing that tau in a normal mouse brain is phosphorylated at many sites that were previously found to be phosphorylated in tau from the brains of patients with AD. PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain

act(p(HGNC:CAMKK2), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Activation of the CAMMK2 pathway has been shown to cause tau proteins to be phosphorylated PubMed:30663117

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(p(HGNC:CAMKK2), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

By activating the CAMMK2 pathway, the β‐ameloid can aid in the phosphorylation of tau proteins and eventually trigger tangles neurofibrillary. PubMed:30663117

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"hydrogen peroxide") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(PUBCHEM:6440944) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y
MeSH
Cerebral Cortex
MeSH
Hippocampus

p(HGNC:TNF) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790

Appears in Networks:
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Experimental Factor Ontology (EFO)
SH-SY5Y
MeSH
Cerebral Cortex
MeSH
Hippocampus

Out-Edges 71

p(HGNC:MAPT, pmod(Ph)) increases a(GO:"neurofibrillary tangle") View Subject | View Object

The neurofibrillary tangles (NFTs) consist largely of hyperphosphorylated twisted filaments of the microtubule-associated protein tau [4,5] PubMed:21214928

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Confidence
High

p(HGNC:MAPT, pmod(Ph)) association bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Annotations
Confidence
High

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

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

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

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Annotations
Confidence
High
MeSH
Neurons

p(HGNC:MAPT, pmod(Ph)) association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

The predominant post-translational modification of tau in the NFTs is phosphorylation; however numerous modifications have been noted including truncation, acetylation, nitration, and several others (2–4). PubMed:24027553

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Text Location
Review

p(HGNC:MAPT, pmod(Ph)) decreases act(a(CHEBI:Thrombin)) View Subject | View Object

Interestingly, phosphorylation of tau also appears to disrupt some thrombin cleavage sites, changing the pattern of cleavage without impeding the thrombin-mediated proteolysis (14, 28). PubMed:24027553

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Text Location
Review

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(HBP:Neurodegeneration) View Subject | View Object

We note that these observed increases in tau phosphorylation occurred well before neuronal death (Fig. 1B), consistent with this pathology representing an early stage in neurodegeneration. PubMed:17403556

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Text Location
Results

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

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MeSH
Post-Synaptic Density
Text Location
Results

p(HGNC:MAPT, pmod(Ph)) association p(HBP:"AT8 tau", pmod(Ph)) View Subject | View Object

Soluble AT8 tau monomers inhibited anterograde FAT (Fig. 6 A, C), while retrograde trans- port was unaffected (Fig. 6 A, D). These data indicate that phos- phorylation of tau at the AT8 epitope, which is associated with hyperphosphorylation of tau in AD and other tauopathies, renders soluble monomeric tau capable of inhibiting antero- grade FAT. PubMed:21734277

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p(HGNC:MAPT, pmod(Ph)) regulates complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding PubMed:21882945

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deg(p(HGNC:MAPT, pmod(Ph))) association p(HGNC:BAG2) View Subject | View Object

However, another related BAG family member, BAG2, interacts with Hsp70 and tau but, unlike BAG1, assists clearance of phosphorylated tau [132] PubMed:21882945

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation act(p(ECCODE:"2.7.11.31")) View Subject | View Object

These results indicate that AMPK activity is impaired by Ab42 in the neuronal cells in which tau phosphor- ylation increased. PubMed:22419736

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association path(MESH:"Retinal Degeneration") View Subject | View Object

These results indicate that AK1 exacerbates rough eye phenotype and tau hyperpho- sphorylation in a tauopathy model organism and that there is a close correlation between the exacerbated rough eye pheno- type and tau phosphorylation. PubMed:22419736

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p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau oligomers") View Subject | View Object

Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation PubMed:28420982

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau oligomers") View Subject | View Object

As hyperphosphorylated tau dislodges from microtubules, its affinity for other tau monomers leads individual tau to bind each other, forming oligomeric tau, a detergent-soluble aggregate PubMed:28420982

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Confidence
High
MeSH
Cerebral Cortex

p(HGNC:MAPT, pmod(Ph)) increases a(GO:"neurofibrillary tangle") View Subject | View Object

Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation PubMed:28420982

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex

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

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004). PubMed:29311797

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MeSH
Cerebral Cortex

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

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

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Annotations
Confidence
High
MeSH
Brain

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

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

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MeSH
Choroid Plexus

p(HGNC:MAPT, pmod(Ph)) increases composite(a(HBP:"Tau antibody, TNT1"), a(HBP:TOC1), p(HGNC:MAPT, pmod(Ph), var("p.S422E")), loc(MESH:Brain)) View Subject | View Object

Staining in fixed tissue sections confirmed several previous reports (Kanaan et al., 2016; Mufson et al., 2014; Patterson et al., 2011a) that pS422 (Fig. 7A) extensively colocalizes with TNT1 (Fig. 7B) and TOC1 (Fig. 7C) in both control and AD brains, despite the relatively sparse appearance of tau pathology in the temporal cortices of control cases (data not shown). PubMed:27373205

Appears in Networks:

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

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

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p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3] PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph)) partOf complex(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) partOf complex(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:

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

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
Disease Ontology (DO)
Down syndrome

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

In PSP cases, both coiled bodies (Fig. 2 D-F) and NFTs (Fig. 2G-I) in the striatum showed a complete co-localisation of PICALM and phosphotau immunoreactivies. PubMed:27260836

Appears in Networks:
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Uberon
striatum
Disease Ontology (DO)
progressive supranuclear palsy

p(HGNC:MAPT, pmod(Ph)) partOf complex(GO:"Pick body") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) partOf complex(GO:"Cajal body") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(p(HGNC:MAPT), p(HGNC:SRC)) View Subject | View Object

The binding of all four SH3 domains tested (from Fyn, p85alpha, PLCgamma1, and the N-terminal SH3 of Grb2) was considerably decreased by phosphorylation. PubMed:18467332

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(p(HGNC:MAPT), p(HGNC:PLCG1)) View Subject | View Object

The binding of all four SH3 domains tested (from Fyn, p85alpha, PLCgamma1, and the N-terminal SH3 of Grb2) was considerably decreased by phosphorylation. PubMed:18467332

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(p(HGNC:GRB2), p(HGNC:MAPT)) View Subject | View Object

The binding of all four SH3 domains tested (from Fyn, p85alpha, PLCgamma1, and the N-terminal SH3 of Grb2) was considerably decreased by phosphorylation. PubMed:18467332

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(p(HGNC:MAPT), p(HGNC:PIK3R1)) View Subject | View Object

The binding of all four SH3 domains tested (from Fyn, p85alpha, PLCgamma1, and the N-terminal SH3 of Grb2) was considerably decreased by phosphorylation. PubMed:18467332

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation rxn(reactants(p(HGNC:MAPT, pmod(Ph))), products(a(CHEBI:"phosphate(3-)"), p(HGNC:MAPT))) View Subject | View Object

Thus, MTs inhibited the rate of tau dephosphorylation by ABaC. PubMed:10464280

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(SFAM:"HSP90 Family") View Subject | View Object

To test the effect of Hsp90 on tau phosphorylation, this protein was mixed with tau protein in the presence of GSK-3 and ATP. Figure 4 shows that tau phosphorylation increases in the presence of increased added amounts of Hsp90. PubMed:19363271

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association p(HGNC:HSPB1) 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

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Annotations
Uberon
temporal cortex

p(HGNC:MAPT, pmod(Ph)) increases complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) 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

Appears in Networks:
Annotations
Uberon
temporal cortex

act(p(HGNC:MAPT, pmod(Ph))) increases bp(GO:"neuron apoptotic process") View Subject | View Object

Taken together, pathological hyperphosphorylated tau caused cell death, and Hsp27 attenuated the cell toxicity of pathological hyperphosphorylated tau. PubMed:14963027

Appears in Networks:
Annotations
Uberon
temporal cortex

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

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) isA complex(p(HGNC:MAPT, pmod(Ph)), p(HGNC:STUB1), p(HGNC:UBE2D2)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation p(HGNC:BAG1) 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

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation complex(p(FPLX:PPP2), p(HGNC:MAPT)) View Subject | View Object

Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo PubMed:23943618

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

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) View Subject | View Object

We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied. PubMed:16630055

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p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:MAPT, pmod(Sumo, Lys, 340)) 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

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation act(p(HGNC:PPP2CA)) View Subject | View Object

Here we show that resveratrol treatment directly interferes with the MID1-α4-PP2A degradation complex by reducing MID1 protein expression in vitro and in vivo. This leads to an increase of microtubule-associated PP2A activity and a time- and dose-dependent dephosphorylation of Tau. Interestingly, we further show that MID1 expression is elevated in AD tissue. PubMed:29062069

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation complex(GO:"tubulin complex") View Subject | View Object

Taken together, these results indicate that the binding of P-Tau to microtubules suppresses its dephosphorylation. PubMed:19401603

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association p(FPLX:PPP2, pmod(Me, Tyr, 307)) View Subject | View Object

Lastly, increased phosphorylation of PP2A at Tyr-307 has been found in P-tau-rich, tangle-bearing neurons from post-mortem brain (Liu et al.,2008b). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) decreases complex(a(GO:"protein phosphatase type 2A complex"), p(HGNC:MAPT)) View Subject | View Object

Notably, tau missense mutations found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17; Goedert et al.,2000) and AD-mimicking tau phosphorylation in proline-rich motifs (Eidenmuller et al.,2001) inhibit the association of tau with PP2A (Figure3B). PubMed:24653673

Appears in Networks:

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

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation a(CHEBI:homocysteine) View Subject | View Object

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

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

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo PubMed:24653673

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

For instance, phosphorylated insoluble tau proteins dampen 26S proteasome activity, while activation of the UPS attenuates tauopathy [27] PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association complex(GO:"proteasome complex") View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

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

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association bp(GO:autophagy) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:MTOR) 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

Appears in Networks:

deg(p(HGNC:MAPT, pmod(Ph))) decreases bp(GO:"neuron death") View Subject | View Object

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

deg(p(HGNC:MAPT, pmod(Ph))) decreases path(HBP:neuroinflammation) View Subject | View Object

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

deg(p(HGNC:MAPT, pmod(Ph))) increases bp(GO:cognition) View Subject | View Object

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:TREM2) 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

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:MAPT, var("p.Ala152Thr")) View Subject | View Object

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers. PubMed:29758300

Appears in Networks:

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

Phosphorylation is generally increased in AD and can be recognized by diagnostic antibodies against phosphoepitopes PubMed:29191965

Appears in Networks:

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

For example, AD brain tau is;4-fold more phosphorylated than normal adult brain tau(93), but a high state of phosphorylation can also occur physiologically (e.g., in fetal brain or in hibernating animals (94). PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Nonetheless, it is assumed that tau aggregation may be driven by phosphorylation at certain sites (95), whereas phosphorylation at other sites may inhibit aggregation (96). PubMed:29191965

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

In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule. PubMed:26631930

Appears in Networks:

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

This view is supported by a recent study showing that tau in a normal mouse brain is phosphorylated at many sites that were previously found to be phosphorylated in tau from the brains of patients with AD. PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) decreases complex(a(MESH:Actins), p(HGNC:MAPT)) View Subject | View Object

The phosphorylation of tau appears to alter its association with actin, as tau phosphorylated at the KXGS motifs tends to colocalize with actin filaments in growth cones during development and in rod-like inclusions of cofilin and actin PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) increases a(GO:"neurofibrillary tangle") View Subject | View Object

By activating the CAMMK2 pathway, the β‐ameloid can aid in the phosphorylation of tau proteins and eventually trigger tangles neurofibrillary. PubMed:30663117

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.