2014
DOI: 10.1038/nm.3700
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Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease

Abstract: Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and t… Show more

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Cited by 391 publications
(480 citation statements)
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“…S5B). Aspariginyl endopeptidase (AEP; also known as legumain) a lysosomal cysteine protease recently implicated in neurodegenerative disease via putative roles in the proteolysis of TDP-43 (32) and Tau (33), also failed to enrich within the axonal lysosome accumulations at amyloid plaques (Fig. 7 D and E).…”
Section: Multiple Lysosomal Proteins Are Enriched Within Plaque-assocmentioning
confidence: 99%
“…S5B). Aspariginyl endopeptidase (AEP; also known as legumain) a lysosomal cysteine protease recently implicated in neurodegenerative disease via putative roles in the proteolysis of TDP-43 (32) and Tau (33), also failed to enrich within the axonal lysosome accumulations at amyloid plaques (Fig. 7 D and E).…”
Section: Multiple Lysosomal Proteins Are Enriched Within Plaque-assocmentioning
confidence: 99%
“…50 The Morris water maze was performed as previously described. 78 All behavior tests were performed in a double-blind manner, and data were acquired using automated computer software.…”
Section: Behavioral Tests and Optogenetic Stimulationmentioning
confidence: 99%
“…78 The Figure 8. Schematics Summarize the Major Findings of the Current Study Accumulation of htau (green) in hippocampus increases miR-92a, which in turn suppresses the translation of vGAT (blue) by binding to its 3 0 UTR, reduces vGATmediated intracellular GABA (purple) loading into the inhibitory vesicles, decreases GABA release at the axon terminals, and thus inhibits the GABAergic functions by suppressing eIPSP and arresting g oscillation activity in hippocampal networks, and finally causes anxiety behaviors.…”
Section: Antibodies Western Blotting and Immunohistochemistry Or Immentioning
confidence: 99%
“…The AEP protease is auto-activated and involves the removal of both C-and N-terminal pro-peptides at varying pH levels [69]. Tau protein undergoes cleavage by AEP at positions N255 and N368 [70]. This cleavage gives rise to several fragments that are unable to bind to MTs but can efficiently aggregate through the exposure of aggregation-prone tau residues i.e.…”
Section: Tau Truncationmentioning
confidence: 99%