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PubMed: 24027553

Title
Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease.
Journal
Frontiers in neurology
Volume
4
Issue
None
Pages
122
Date
2013-09-03
Authors
Pritchard SM | Johnson GV | Chesser AS

Evidence c414a69939
JSON

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

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

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a(CHEBI:"N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal") decreases act(a(CHEBI:"Hsp90 inhibitor")) View Subject | View Object

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Evidence cebb972674
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In M1C neuroblastoma cells that inducibly express wild-type full-length tau (4R0N), EPX, and MG-132 induced accumulation of full-length tau but there was a concomitant loss of C-terminus immunoreactivity (64).

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

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

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Evidence 2eef150c24
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Also, treating primary hippocampal neurons with pre-aggregated amyloid beta (Abeta) led to the generation of tau fragments of ∼35, ∼24, and ∼17 kDa, which was blocked by addition of a calpain inhibitor (52, 53). Tau fragments of the same size were also found in AD brain tissue (19).

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "35kD")) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "24kD")) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"calpain inhibitor") decreases p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"calpain inhibitor") decreases p(HGNC:MAPT, frag("?", "35kD")) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"calpain inhibitor") decreases p(HGNC:MAPT, frag("?", "24kD")) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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a(CHEBI:"calpain inhibitor") decreases act(p(HGNCGENEFAMILY:Calpains)) View Subject | View Object

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Hippocampus
MeSH
Alzheimer Disease
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Evidence c54024bf6d
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Calpains are calcium-activated cytosolic cysteine proteases. Two isoforms differentiated and named by their sensitivities to calcium (i.e., μ-calpain and m-calpain, also called calpain-1 and calpain-2) are abundant in the central nervous system, and respond to micromolar and millimolar concentrations of calcium, respectively (45). Calpain has been implicated in a number of neurodegenerative diseases [for a review, see (46)].

a(CHEBI:"calcium(2+)") increases act(p(HGNCGENEFAMILY:Calpains)) View Subject | View Object

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p(HGNCGENEFAMILY:Calpains) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNCGENEFAMILY:Calpains) View Subject | View Object

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Evidence b8c232d844
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Excitotoxicity leading to elevated intracellular calcium is a common feature of neurodegenerative diseases, and is implicated in AD (49, 50). This process may lead to enhanced activation of calpains (51). This in turn could influence a number of pathologic processes, including tau proteolysis. Indeed, tau has a number of putative calpain cleavage sites, and incubation of recombinant tau with calpain generates specific fragments, including one that is ∼35 kDa and one that is ∼17 kDa (19, 20).

a(CHEBI:"calcium(2+)", loc(GO:intracellular)) increases act(p(HGNCGENEFAMILY:Calpains)) View Subject | View Object

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Alzheimer Disease
MeSH
Neurodegenerative Diseases
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bp(HBP:Excitotoxicity) increases a(CHEBI:"calcium(2+)", loc(GO:intracellular)) View Subject | View Object

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Alzheimer Disease
MeSH
Neurodegenerative Diseases
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act(p(HGNCGENEFAMILY:Calpains)) increases deg(p(HGNC:MAPT)) View Subject | View Object

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Alzheimer Disease
MeSH
Neurodegenerative Diseases
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act(p(HGNCGENEFAMILY:Calpains)) increases p(HGNC:MAPT, frag("?", "35kD")) View Subject | View Object

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Alzheimer Disease
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Neurodegenerative Diseases
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act(p(HGNCGENEFAMILY:Calpains)) increases p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

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Alzheimer Disease
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Neurodegenerative Diseases
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Evidence 1bd2882787
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Increasing intracellular calcium levels in PC12 cells leads to calpain-induced cleavage of tau (18). This may reflect a potential effect of excitotoxicity in AD. Inducing apoptosis in cerebellar granule cells yields calpain-mediated tau fragments, including a dominant ∼17 kDa fragment (17).

a(CHEBI:"calcium(2+)", loc(GO:intracellular)) increases act(p(HGNCGENEFAMILY:Calpains)) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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a(HBP:Excitotoxicity) association act(p(HGNCGENEFAMILY:Calpains)) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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bp(GO:"apoptotic process") association p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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p(HGNC:MAPT, frag("?", "17kD")) association bp(GO:"apoptotic process") View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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act(p(HGNCGENEFAMILY:Calpains)) increases deg(p(HGNC:MAPT)) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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act(p(HGNCGENEFAMILY:Calpains)) increases p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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act(p(HGNCGENEFAMILY:Calpains)) association a(HBP:Excitotoxicity) View Subject | View Object

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Experimental Factor Ontology (EFO)
PC12
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Evidence a5080177f0
JSON

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).

a(CHEBI:"methylene blue") increases bp(MESH:Autophagy) View Subject | View Object

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

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Hippocampus
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bp(MESH:Autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

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Hippocampus
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Evidence 4fc20c2451
JSON

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

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

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

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

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

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

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Evidence 58966fc696
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Evidence supporting a role for thrombin in tau proteolysis came initially from an in vitro study showing that thrombin degraded recombinant full-length tau from the N-terminus yielding a 25-kDa fragment, while preserving the microtubule binding repeat domain (13).

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

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act(a(CHEBI:Thrombin)) increases p(HGNC:MAPT, frag("1_?")) View Subject | View Object

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act(a(CHEBI:Thrombin)) causesNoChange p(HGNC:MAPT, frag("561_685")) View Subject | View Object

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Evidence d372c856e3
JSON

Thrombin is a serine protease that is a well characterized component of the coagulation cascade. It is typically produced and secreted by endothelial cells, including those in the brain in response to hemodynamic injury.

a(CHEBI:Thrombin) increases bp(GO:coagulation) View Subject | View Object

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Brain
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a(MESH:"Endothelial Cells") increases sec(a(CHEBI:Thrombin)) View Subject | View Object

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Brain
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Evidence 93314dbd78
JSON

A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36)

a(CHEBI:Thrombin) increases bp(HBP:"neurite retraction") View Subject | View Object

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a(CHEBI:Thrombin) increases bp(GO:"apoptotic process") View Subject | View Object

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path(MESH:"Alzheimer Disease") increases a(CHEBI:Thrombin, loc(MESH:Microvessels)) View Subject | View Object

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Brain
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path(MESH:"Alzheimer Disease") increases a(CHEBI:Thrombin, loc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

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Evidence 1e43eda51b
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Thrombin may also be influencing tau pathology, as treatment of immortalized hippocampal neuronal cells (HT22 cells) with thrombin resulted in the formation of thioflavin-S positive tau aggregates within 24 h, followed by an increase in cell death at 72 h (37).

a(CHEBI:Thrombin) increases bp(GO:"apoptotic process") View Subject | View Object

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Hippocampus
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a(CHEBI:Thrombin) increases a(HBP:"Tau aggregates") View Subject | View Object

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Hippocampus
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Evidence 6633865a33
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There are also data to suggest that thrombin may act intracellularly to mediate tau pathology. Thrombin is expressed within neurons and astrocytes in both normal and AD brain (38). In AD brain the staining pattern for thrombin and prothrombin was characteristic of the pattern of NFTs, although these structures were not colabeled with antibodies for tau (38).

a(CHEBI:Thrombin) association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Alzheimer Disease
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path(MESH:"Neurofibrillary Tangles") association a(CHEBI:Thrombin) View Subject | View Object

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Alzheimer Disease
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Evidence 86d64b84ad
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A later study, however, showed that in N2a neuroblastoma cells expressing a construct of only the tau repeat domain, thrombin cleavage could still occur, indicating additional cleavage sites (15). Similar results were observed in an in vitro assay (15).

act(a(CHEBI:Thrombin)) increases deg(p(HGNC:MAPT, frag("561_685"))) View Subject | View Object

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Evidence de47c66de6
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Thrombin signaling can also activate caspases (36). Proteasomal impairment appears to be upstream of caspase activation, as inhibiting the proteasome with epoxomicin (EPX) led to activation of caspase-3 in primary neurons (63) and in a neuroblastoma cell line expressing wild-type tau (64).

act(a(CHEBI:Thrombin)) increases act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

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a(CHEBI:epoxomicin) increases act(p(HGNC:CASP3)) View Subject | View Object

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Evidence 7968114058
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Treating hippocampal slices with chloroquine (CQ), which raises the pH of lysosomes to impair enzymatic function, was associated with increased levels of full-length tau (89, 91).

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

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Hippocampus
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Evidence 423c922ef7
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In a cell line expressing the repeat domain of tau containing the FTDP-17ΔK280 mutant, treatment with the disaccharide trehalose, an mTor-independent autophagy activator, significantly reduced aggregated tau as measured by Thioflavin-S staining, as well as total tau levels both soluble and insoluble as detected by western blotting (96).

a(MESH:Trehalose) increases bp(MESH:Autophagy) View Subject | View Object

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Frontotemporal Dementia
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a(MESH:Trehalose) decreases a(HBP:"Tau aggregates") View Subject | View Object

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

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Frontotemporal Dementia
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Evidence ecd81288e9
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In M1C neuroblastoma cells that inducibly express full-length wild-type tau (4R0N), treatment with CQ also significantly slowed down tau degradation, and caused its accumulation (92). Treatment of hippocampal slices with the cathepsin modulator ZPAD (which stimulates cathepsin D very strongly) appears to increase the proteolysis of full-length tau resulting in the production of smaller fragments, including a phosphorylated 29 kDa fragment (86, 89). This partial degradation of tau was inhibited by inclusion of a selective cathepsin D inhibitor (86).

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

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

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act(p(HGNC:CTSD)) increases p(HGNC:MAPT, frag("?", "29kD"), pmod(Ph)) View Subject | View Object

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Evidence c5e8ce64b0
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Similarly, overexpressing the FTDP-17 mutant P301L tau in SH-SY5Y cells and then treating with lactacystin led to significantly increased tau levels (70). Lactacystin also caused accumulation of endogenous tau in the HT22 murine neuronal cell line (71). In immortalized mouse cortical neuronal cells inducibly expressing full-length wild-type tau, EPX slowed the degradation of full-length tau (72).

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

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a(CHEBI:lactacystin) increases p(HGNC:MAPT, var("p.P301L")) View Subject | View Object

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Evidence 6821f329eb
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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).

a(CHEBI:geldanamycin) increases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

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

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Evidence 34a213a049
JSON

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

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

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Evidence f838f30bd0
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Additionally, incubation of rat brain extract (containing endogenous tau and proteasomal enzymes) with the proteasome activators Mg2+ and ATP resulted in lower total tau levels with an increase in smaller forms, compared to extract not supplemented with Mg2+ and ATP (73). The loss of tau was blocked by lactacystin giving further evidence that the proteasome was degrading tau (73).

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

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a(CHEBI:lactacystin) decreases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

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

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Evidence 635c6c08c0
JSON

Stimulating autophagy either through serum withdrawal or rapamycin treatment in SH-SY5Y cells overexpressing P301L tau that had been induced to aggregate led to substantial reduction in aggregates that was prevented by 3-MA (70).

a(CHEBI:sirolimus) increases bp(MESH:Autophagy) View Subject | View Object

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bp(MESH:Autophagy) decreases a(HBP:"Tau aggregates") View Subject | View Object

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bp(MESH:Autophagy) decreases p(HGNC:MAPT, var("p.P301L")) View Subject | View Object

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Evidence 4a3b4ec817
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Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1).

a(HBP:"Tau aggregates") increases path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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

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

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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path(MESH:"Neurofibrillary Tangles") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 1d0ab52d5f
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Thrombin cleavage of the repeat domain construct yielded fragments that rapidly aggregated, which closely correlated with toxicity in cell culture (15). These fragments can also induce the aggregation of full-length tau (39).

a(HBP:"Tau aggregates") positiveCorrelation path(HBP:neurotoxicity) View Subject | View Object

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deg(p(HGNC:MAPT, frag("561_685"))) increases a(HBP:"Tau aggregates") View Subject | View Object

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path(HBP:neurotoxicity) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

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Evidence ecea25fb6a
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This may suggest that abnormal proteins themselves may interfere with proteasomal degradative processes. Indeed, in vitro aggregated paired helical filament tau could inhibit proteasome activity (69).

a(HBP:"Tau aggregates") decreases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

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Evidence 5c749cd2c3
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Electron microscopic analysis of brain tissue from confirmed AD cases revealed that AVs accumulated in dystrophic neurites and correlated with the presence of filamentous tau (79). However, this correlation was not quantified (79).Similar results were observed in mouse models of AD.

a(HBP:"Tau aggregates") positiveCorrelation a(MESH:Autophagosomes) View Subject | View Object

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Alzheimer Disease
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a(MESH:Autophagosomes) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

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Alzheimer Disease
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Evidence 1c0a491d70
JSON

Overexpressing only the repeat domain of tau containing an FTDP-17 mutation in neuroblastoma cells leads to tau aggregation as well as the appearance of smaller proteolytic fragments. Using the autophagy inhibitor 3-methyladenine (3-MA) to block the formation of autophagosomes led to an increase in both soluble and insoluble tau (94).

a(MESH:"3-methyladenine") decreases bp(MESH:Autophagy) View Subject | View Object

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Frontotemporal Dementia
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a(MESH:"3-methyladenine") increases p(HGNC:MAPT, frag("?")) View Subject | View Object

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Frontotemporal Dementia
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p(HGNC:MAPT, frag("561_685")) increases a(HBP:"Tau aggregates") View Subject | View Object

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Frontotemporal Dementia
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Evidence 36b090719d
JSON

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

a(MESH:"9-deoxy-delta-9-prostaglandin D2") increases act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

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

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act(p(HGNCGENEFAMILY:Caspases)) association path(MESH:Inflammation) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:Inflammation) association act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

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Evidence f695ac4b56
JSON

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

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

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

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Evidence caad5d3341
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Aminopeptidases are a group of enzymes that cleave from the N-terminal end of a protein. The family includes alanyl, arginyl, and glutamyl peptidases. Puromycin sensitive aminopeptidase (PSA) is an alanyl peptidase that is responsible for s90% of the aminopeptidase activity in the brain(10).

a(MESH:Brain) association act(p(HGNC:NPEPPS)) View Subject | View Object

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act(p(HGNC:NPEPPS)) association a(MESH:Brain) View Subject | View Object

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Evidence 666596257b
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This demonstrates that in the absence of mutant PS1, AD-associated impairment in autophagy occurs and thus is due to other factors. Treatment of ex vivo hippocampal slice cultures with lysosomal disruptors causes the formation of enlarged, dystrophic neurites filled with AVs and lysosomes, similar to what is seen in mouse AD models and human AD tissue (85, 86)

a(MESH:Lysosomes) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(MESH:Autophagy) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation bp(MESH:Autophagy) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation a(MESH:Lysosomes) View Subject | View Object

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Evidence f538f785e6
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Tubulin was later identified as a substrate for HTRA1, suggesting HTRA1 may be involved in mediating microtubule function (42, 43). A more recent study showed that HTRA1 can cleave recombinant tau in vitro into multiple fragments of varying sizes, and furthermore can degrade insoluble and fibrillarized tau (16).

act(a(MESH:Microtubules)) association act(p(HGNC:HTRA1)) View Subject | View Object

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

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

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act(p(HGNC:HTRA1)) association act(a(MESH:Microtubules)) View Subject | View Object

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act(p(HGNC:HTRA1)) increases deg(a(HBP:"Tau fibrils")) View Subject | View Object

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act(p(HGNC:HTRA1)) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

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Evidence df0c4ff884
JSON

In a mouse model expressing the FTDP-17 mutant P301S, promoting autophagy with trehalose treatment beginning at weaning significantly reduced insoluble tau, as well as tau phosphorylated at T212/S214 (AT100) (97). However, no other phosphorylation sites were assessed. This effect was correlated with improved neuronal survival in cortical layers I–III (97).

a(MESH:Trehalose) increases bp(MESH:Autophagy) View Subject | View Object

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Frontotemporal Dementia
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bp(GO:"neuron death") negativeCorrelation bp(MESH:Autophagy) View Subject | View Object

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Frontotemporal Dementia
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bp(MESH:Autophagy) decreases p(MGI:Mapt, var("p.P301S")) View Subject | View Object

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Frontotemporal Dementia
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bp(MESH:Autophagy) decreases p(MGI:Mapt, pmod(Ph, Thr, 212), var("p.P301S")) View Subject | View Object

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Frontotemporal Dementia
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bp(MESH:Autophagy) decreases p(MGI:Mapt, pmod(Ph, Ser, 214), var("p.P301S")) View Subject | View Object

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Frontotemporal Dementia
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bp(MESH:Autophagy) negativeCorrelation bp(GO:"neuron death") View Subject | View Object

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MeSH
Frontotemporal Dementia
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Evidence 07acd81bb6
JSON

Activating autophagy with trehalose in rat cortical neurons demonstrated certain phospho-epitopes (AT8, PHF1, and 12E8) were reduced more significantly than total tau – up to 80% compared to the 20% reduction in total tau (96).

a(MESH:Trehalose) increases bp(MESH:Autophagy) View Subject | View Object

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bp(MESH:Autophagy) decreases a(HBP:"Tau epitope, AT8") View Subject | View Object

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bp(MESH:Autophagy) decreases a(HBP:"Tau epitope, PHF1") View Subject | View Object

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bp(MESH:Autophagy) decreases a(HBP:"Tau epitope, 12E8") View Subject | View Object

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Evidence 8a3df081fa
JSON

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

bp(GO:"apoptotic process") increases act(p(HGNC:CASP6)) View Subject | View Object

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

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act(p(HGNC:CASP3)) increases p(HBP:"Tau C3") View Subject | View Object

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p(HBP:"Tau C3") increases bp(GO:"apoptotic process") View Subject | View Object

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Evidence a810be2a0d
JSON

The accumulation of proteins in AD patients’ brains generated interest in the role of proteasomal function. There is evidence suggesting that proteasomal activity, but not protein level, is decreased in AD-sensitive brain regions specifically compared to unaffected regions (68, 69).

bp(GO:"proteasomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"proteasomal protein catabolic process") View Subject | View Object

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Evidence e1e253c156
JSON

Mutations in PS1 were shown to impair the acidification of lysosomes, which is necessary for activating the proteolytic enzymes in this compartment. Improper acidification and impaired proteolysis of substrates would compromise the autophagy system and result in the accumulation of AVs as described above.

bp(GO:"vacuolar acidification") increases bp(GO:proteolysis) View Subject | View Object

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p(HGNC:PSEN1) increases bp(GO:"vacuolar acidification") View Subject | View Object

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Evidence 7be8ee94ec
JSON

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

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

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

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

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MeSH
Huntington Disease
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p(HGNC:NPEPPS) association bp(GO:autophagy) View Subject | View Object

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MeSH
Huntington Disease
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Evidence a52245b79c
JSON

Furthermore, active caspase co-localizes to NFTs (58), and caspase-cleaved tau is found in AD-affected brain regions, particularly in neurons displaying tangle pathology (59, 60). This includes tau cleaved by caspase-6 in the C-terminus (58–60) as well as in the N-terminus (24). TauC3 is present in AD brain – in neurons and co-localized with NFTs – and inversely correlates with cognitive function (55, 60, 61).

bp(GO:cognition) negativeCorrelation p(HBP:"Tau C3") View Subject | View Object

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Alzheimer Disease
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p(HBP:"Tau C3") negativeCorrelation bp(GO:cognition) View Subject | View Object

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Alzheimer Disease
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act(p(HGNC:CASP6)) increases p(HGNC:MAPT, frag("?_*")) View Subject | View Object

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Alzheimer Disease
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act(p(HGNC:CASP6)) increases p(HGNC:MAPT, frag("1_?")) View Subject | View Object

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Alzheimer Disease
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act(p(HGNCGENEFAMILY:Caspases)) association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Alzheimer Disease
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path(MESH:"Neurofibrillary Tangles") association act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

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Alzheimer Disease
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Evidence 21219cd810
JSON

Another serine protease recently implicated in tau processing is HTRA1. This is a ubiquitously expressed, ATP-independent intracellular protease. Expression is detectable in many tissues, including the nervous system, although expression is low (40).Nonetheless, this enzyme was initially implicated in AD because it may play a role in amyloid processing (41).

bp(HBP:"APP processing") association p(HGNC:HTRA1) View Subject | View Object

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bp(HBP:"APP processing") association path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:HTRA1) association bp(HBP:"APP processing") View Subject | View Object

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path(MESH:"Alzheimer Disease") association bp(HBP:"APP processing") View Subject | View Object

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Evidence bfa4e256ff
JSON

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).

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

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Hippocampus
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bp(MESH:Autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

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Hippocampus
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Evidence f143b6ba75
JSON

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

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

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bp(MESH:Autophagy) increases deg(p(HBP:"Tau C3")) View Subject | View Object

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

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Evidence e56264aad3
JSON

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

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

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

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act(p(HGNCGENEFAMILY:Proteasome)) causesNoChange deg(a(HBP:"Tau aggregates")) View Subject | View Object

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Alzheimer Disease
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Evidence b249696d5d
JSON

For example, as discussed above, certain modified forms of tau, such as caspase-cleaved tau, have a stronger tendency to aggregate. As tau begins to assemble into oligomers, it may become increasingly undesirable as a proteasomal substrate. These low-order, soluble oligomers may be preferentially degraded by autophagy.

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

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bp(MESH:Autophagy) increases deg(a(HBP:"Tau oligomers")) View Subject | View Object

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act(p(HGNCGENEFAMILY:Proteasome)) causesNoChange deg(a(HBP:"Tau oligomers")) View Subject | View Object

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p(HBP:"Tau C3") increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence 31c6b98c71
JSON

Finally, caspase-3 cleaved tau has a shorter half-life than full-length tau and is preferentially degraded by autophagy (72).

bp(MESH:Autophagy) decreases p(HBP:"Tau C3") View Subject | View Object

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Evidence 8fb79d53c5
JSON

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

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

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

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Evidence 861d91c73e
JSON

Given that in animal models of AD reducing tau levels attenuates neuronal dysfunction (7, 8), and in humans the extent of tau pathology correlates with cognitive decline (9), there is a growing interest in defining the degradative pathways that remove tau from the cell.

p(HGNC:MAPT) increases path(MESH:"Nerve Degeneration") View Subject | View Object

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Alzheimer Disease
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path(MESH:"Cognitive Dysfunction") positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

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Alzheimer Disease
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path(MESH:Tauopathies) positiveCorrelation path(MESH:"Cognitive Dysfunction") View Subject | View Object

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Alzheimer Disease
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Evidence 2254c76468
JSON

For example, if HEK cells are transfected with tau and ubiquitin, tau is readily ubiquitylated and degraded by the proteasome (66).

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

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composite(a(MESH:Ubiquitin), p(HGNC:MAPT)) increases p(HGNC:MAPT, pmod(Ub)) View Subject | View Object

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Evidence a0ae06ac7a
JSON

For example, in the study where rat brain extract was incubated with Mg2+ and ATP, there was an overall decrease in tau due to proteasomal activity; however tau phosphorylated at the PHF1 and Tau-1 epitopes seemed to be preferentially degraded as they were non-detectable within 3 h (73). The preferential degradation of specific phospho-forms of tau by a particular pathway has been reported in other studies as well.

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(RGD:Mapt)) View Subject | View Object

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Brain
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act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(RGD:Mapt, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404))) View Subject | View Object

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Brain
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composite(a(CHEBI:"magnesium(2+)"), a(CHEBI:ATP)) increases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

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Brain
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Evidence f3c4705197
JSON

Furthermore, expressing a cleavage resistant form of tau (D421E) protects cells from apoptotic cell death (22). Another potential mechanism of inducing caspase-3 cleavage of tau is the presence of Aβ peptides. TauC3 is formed in primary cortical neurons after treatment with Aβ (23).

composite(p(HBP:"amyloid-beta oligomers"), p(HGNC:CASP3)) increases p(HBP:"Tau C3") View Subject | View Object

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p(HGNC:MAPT, var("p.D421E")) decreases bp(GO:"apoptotic process") View Subject | View Object

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Evidence 51b351f290
JSON

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

act(p(HGNC:CASP3)) increases p(HGNC:MAPT, frag("?_*")) View Subject | View Object

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act(p(HGNC:CASP6)) increases p(HGNC:MAPT, frag("?_*")) View Subject | View Object

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

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MeSH
Alzheimer Disease
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Review

Evidence 2467920d3b
JSON

Caspase cleavage of tau may play a role in stimulating the tau aggregation seen in AD. Indeed, in vitro polymerization assays demonstrate that caspase-cleaved tau has a greater propensity to aggregate compared to full-length tau (23, 55).

act(p(HGNC:CASP3)) increases p(HBP:"Tau C3") View Subject | View Object

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Alzheimer Disease
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p(HBP:"Tau C3") increases a(HBP:"Tau aggregates") View Subject | View Object

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Alzheimer Disease
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Evidence e0ae049758
JSON

In order for caspase to cleave tau in the AD brain, it needs to be present in its active form. The active forms of both caspase-3 and caspase-6 are elevated in AD-specific brain regions (temporal and frontal lobes) compared to unaffected regions (cerebellum) and control brains (57, 58).

act(p(HGNC:CASP3)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Frontal Lobe
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Temporal Lobe
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act(p(HGNC:CASP6)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Frontal Lobe
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Temporal Lobe
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path(MESH:"Alzheimer Disease") positiveCorrelation act(p(HGNC:CASP3)) View Subject | View Object

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Frontal Lobe
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Temporal Lobe
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path(MESH:"Alzheimer Disease") positiveCorrelation act(p(HGNC:CASP6)) View Subject | View Object

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Frontal Lobe
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Temporal Lobe
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Evidence 61b65adf5e
JSON

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

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

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

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Evidence 15d889f957
JSON

Similarly, adding exogenous cathepsin D to homogenates of rat cortex at a neutral pH also generated tau fragments. Intriguingly, if a cysteine protease inhibitor was added to the assay, tau cleavage stopped at the 29-kDa fragment, suggesting that cathepsin D (an aspartyl protease) could cleave tau to a 29-kDa fragment after which other proteases may act to further degrade the protein.

act(p(HGNC:CTSD)) increases p(HGNC:MAPT, frag("?", "29kD")) View Subject | View Object

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Evidence 5bc806f7f1
JSON

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

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

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Tauopathies
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act(p(HGNC:CTSD)) increases path(MESH:Neuroprotection) View Subject | View Object

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Tauopathies
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act(p(HGNC:CTSD)) decreases path(HBP:neurotoxicity) View Subject | View Object

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Tauopathies
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Evidence ad41c33474
JSON

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).

p(HBP:"cis p-tau") decreases deg(p(HBP:"cis p-tau")) View Subject | View Object

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p(HBP:"cis p-tau") decreases act(p(HGNC:PIN1)) View Subject | View Object

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

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Evidence cfe9e46638
JSON

The active form of calpain-2 is found in 50–75% of NFTs in tauopathies including AD, but not in protein aggregates found in other diseases (47). This is consistent with another study that found equivalent calpain levels between control and AD cases, but the activity level of the enzyme isolated from AD brain tissue was increased (48).

p(HGNC:CAPN2) positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Alzheimer Disease
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Tauopathies
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path(MESH:"Alzheimer Disease") increases act(p(HGNC:CAPN2)) View Subject | View Object

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Alzheimer Disease
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Tauopathies
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path(MESH:"Neurofibrillary Tangles") positiveCorrelation p(HGNC:CAPN2) View Subject | View Object

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MeSH
Alzheimer Disease
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Tauopathies
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Evidence 7699447b7c
JSON

Caspase-6 was also shown to cleave the N-terminus of tau in vitro (24). Caspase-3, which is a key effector in the apoptotic cascade, cleaves tau predominantly at the C-terminal D421 site generating a fragment often referred to as tauC3 (22, 23).

act(p(HGNC:CASP6)) increases p(HGNC:MAPT, frag("1_?")) View Subject | View Object

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act(p(HGNC:CASP6)) increases bp(GO:"apoptotic process") View Subject | View Object

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act(p(HGNC:CASP6)) increases p(HGNC:MAPT, var("p.D421*")) View Subject | View Object

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Evidence 5fa5f54e5c
JSON

In these transgenic mice LC3-positive bodies were particularly apparent in neurites surrounding amyloid plaques, and immunoblotting of hippocampi from 6 month old transgenic PS1/APP mice revealed increased levels of LC3-II compared to wild-type mice (81)

p(HGNC:MAP1LC3A) positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

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path(MESH:"Plaque, Amyloid") positiveCorrelation p(HGNC:MAP1LC3A) View Subject | View Object

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Evidence 87f9f50feb
JSON

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).

p(HGNC:MAPT, frag("1_?")) association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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p(HGNC:MAPT, frag("?_*")) association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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

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

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

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

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

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

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path(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT, frag("1_?")) View Subject | View Object

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path(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT, frag("?_*")) View Subject | View Object

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Evidence 75d8ce55a9
JSON

On the one hand, expressing a 17-kDa fragment of tau based on calpain cleavage site mapping in hippocampal neurons led to neurite retraction and the appearance of varicosities after 48 h (52). Additionally, suppressing calpain activity in a fly model of tauopathy prevented neurodegeneration, as did expressing a calpain-resistant form of tau (54).

p(HGNC:MAPT, frag("?", "17kD")) increases bp(HBP:"neurite retraction") View Subject | View Object

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Hippocampus
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act(p(HGNCGENEFAMILY:Calpains)) increases path(HBP:Neurodegeneration) View Subject | View Object

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Tauopathies
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Evidence 766597422b
JSON

In contrast, another study used mass spectroscopy and sequencing to identify the “17 kDa” tau cleavage product and found it did not correspond to the recombinant fragment utilized in the above studies (19). Expression of a recombinant form of the mass spectroscopy-identified fragment in hippocampal neurons was not toxic (19).

p(HGNC:MAPT, frag("?", "17kD")) causesNoChange path(HBP:neurotoxicity) View Subject | View Object

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Evidence a3289967f2
JSON

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).

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

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Evidence 8716765466
JSON

However, another study, also using HEK cells and ubiquitin K48 and K63 mutants, demonstrated that in the presence of the E3 ligase CHIP, tau could be ubiquitylated by both K48 and K63 linkages (100). The likelihood that in vivo tau can be ubiquitylated in multiple ways is supported by studies showing tau isolated from NFTs in human brain has several forms of ubiquitin linkages as well as mono-ubiquitylation (101, 102). These data suggest that the physical structure of the ubiquitin chain is unlikely to be a sufficient signal for selectively targeting tau to either the proteasome or autophagy.

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

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

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

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Evidence b13c4d6c12
JSON

PSA was identified as a potential player in tau pathology through a microarray analysis of gene expression in disease-vulnerable vs. disease-resistant brain regions in JNPL3 mice that overexpress a mutant form of tau (P301L) found in the disease frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These mice develop neurodegeneration in the cortex while the cerebellum is relatively spared [although in the original description of these animals pathology was found in the deep cerebellar nuclei (27)].

p(HGNC:MAPT, var("p.P301L")) association path(MESH:"Frontotemporal Dementia") View Subject | View Object

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p(MGI:Mapt, var("p.P301L")) association path(HBP:Neurodegeneration) View Subject | View Object

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Cerebral Cortex
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path(HBP:Neurodegeneration) association p(MGI:Mapt, var("p.P301L")) View Subject | View Object

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Cerebral Cortex
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path(MESH:"Frontotemporal Dementia") association p(HGNC:MAPT, var("p.P301L")) View Subject | View Object

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Evidence c6c70e0a1c
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Interestingly, PSA was found to be elevated in the cerebellum of these TAUP301L mice (10). The levels of PSA are also higher in human cerebellum compared to cortex in both controls and FTD cases. A slight elevation in PSA was also observed in FTD cortices compared to controls.

p(HGNC:NPEPPS) positiveCorrelation p(MGI:Mapt, var("p.P301L")) View Subject | View Object

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

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Cerebellum
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p(MGI:Mapt, var("p.P301L")) positiveCorrelation p(HGNC:NPEPPS) View Subject | View Object

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

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Cerebellum
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Evidence dfae3799a5
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In addition, a non-functional PSA mutant exacerbated tau pathology in a Drosophila model of tauopathy, while overexpressing PSA ameliorated the tau phenotype and diminished tau levels (10). Overexpressing PSA had a similar effect in the TAUP301L mice, reducing the pathologic phenotype (delaying paralysis, increasing motor neuron density in the spinal cord, decreasing gliosis) and decreasing tau levels (12).

p(HGNC:NPEPPS) decreases p(MGI:Mapt, var("p.P301L")) View Subject | View Object

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p(HGNC:NPEPPS) decreases path(MESH:Tauopathies) View Subject | View Object

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

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p(HGNC:NPEPPS) decreases path(MESH:Paralysis) View Subject | View Object

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p(HGNC:NPEPPS) decreases path(MESH:Gliosis) View Subject | View Object

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Evidence 7ff907515e
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For example, it has been shown that the isomerase Pin1, which has been implicated in AD (30), had opposite effects on P301L and wild-type tau degradation (31). An alternative explanation for the effects of PSA may be that PSA is indirectly regulating tau degradation.

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

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p(HGNC:PIN1) association path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:PIN1) decreases deg(p(HGNC:MAPT, var("p.P301L"))) View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNC:PIN1) View Subject | View Object

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Evidence 1c32b183e6
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PSA was able to cleave recombinant tau in vitro, as well as tau from control human brain (11). However, the data presented in this study suggest that PSA is cleaving tau from both the C- and N-terminal ends, which is not expected from an aminopeptidase. Additionally, other studies failed to demonstrate tau cleavage by PSA (28, 29).

p(HGNC:NPEPPS) increases p(HGNC:MAPT, frag("1_?")) View Subject | View Object

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Brain
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p(HGNC:NPEPPS) increases p(HGNC:MAPT, frag("?_*")) View Subject | View Object

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Brain
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Evidence ecc35da624
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It is well established that mutations in PS1 result in familial AD, and until recently it was thought that this was only due to alterations in APP processing.

p(HGNC:PSEN1) association path(MESH:"Alzheimer disease, familial, type 3") View Subject | View Object

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path(MESH:"Alzheimer disease, familial, type 3") association p(HGNC:PSEN1) View Subject | View Object

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Evidence e539d33303
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There was a strong correlation between active caspases and the presence of tangles within viable neurons. In the few cells found that were caspase-positive and tangle-negative, 88% had tangles within 24 h (56). This seems to further support a role for caspase cleavage in the evolution of tau pathology.

act(p(HGNCGENEFAMILY:Caspases)) positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Neurons
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path(MESH:"Neurofibrillary Tangles") positiveCorrelation act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

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Neurons
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Evidence ccc5bb4fcc
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In both studies caspase activation correlated with the appearance and increase over time of caspase-cleaved tau species, which appeared to subsequently form aggregates in the neurons (63). While the mechanism is unclear, a possibility is that accumulating proteins might be a factor in initiating caspase activation.

act(p(HGNCGENEFAMILY:Caspases)) increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence b65067f549
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Mice in which the critical autophagy gene Atg7 is knocked out in forebrain neurons develop age-dependent neurodegeneration with accumulation of phosphorylated tau within intracellular inclusions (99). These inclusions specifically contained tau phosphorylated at AT8, AT100, and TG3 epitopes, but not PHF1. Significantly, if tau was also knocked out in these autophagy-deficient mice, neurodegeneration was reduced (99).

p(MGI:Atg7) decreases path(HBP:Neurodegeneration) View Subject | View Object

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p(MGI:Atg7) decreases p(MGI:Mapt, pmod(Ph)) View Subject | View Object

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Neurons
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p(MGI:Atg7) decreases p(MGI:Mapt, pmod(Ph, Ser, 214), pmod(Ph, Thr, 212)) View Subject | View Object

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Neurons
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p(MGI:Atg7) decreases p(MGI:Mapt, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

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Neurons
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p(MGI:Atg7) decreases p(MGI:Mapt, pmod(Ph, Thr, 231)) View Subject | View Object

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Neurons
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p(MGI:Mapt, pmod(Ph)) increases path(HBP:Neurodegeneration) View Subject | View Object

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Neurons
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Evidence 2d335146b7
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Additionally, tau appears to be physically associated with the proteasome in brain tissue from AD cases. When tau was immunoprecipitated it pulled down both the 26S and 20S proteasomes, while immunoprecipitating for the 20S catalytic core pulled down tau (69).

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

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Evidence 21eea0bb01
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However, as previously discussed, autophagy is likely impaired in AD. The tendency for certain phospho-epitopes to show preferential clearance by certain pathways may also relate to their propensity for aggregation.

path(MESH:"Alzheimer Disease") decreases bp(MESH:Autophagy) View Subject | View Object

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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.