Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease
Open accessAbstract
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 triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.
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Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling.
“Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling5, 6, 14, 22, 40–43.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [43]
The Introduction and Results discuss tau’s effects on microtubules and the formation of tau filaments, not binding to filamentous actin. Searches for actin, MAP2, cross-linking, and bundling found no passage in our copy addressing the claimed effect. (LLM, conf=0.75)
Experimental — accuracy not yet measuredTau can be cleaved by AEP at Asn167, Asn255, and Asn368.
“Tau can be cleaved by AEP at Asn167, Asn255, and Asn368 [212, 213].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
AEP cleaves tau without inducing tau accumulation in microglia.
“AEP cleaves tau without inducing tau accumulation in microglia.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
A recent study finds no change in soluble tau-368 in AD patient brain, and only trace amounts of tau-368 were observed in insoluble tau aggregates in AD brain.
“However, a recent study finds no change in soluble tau-368 in AD patient brain, and only trace amounts of tau-368 were observed in insoluble tau aggregates in AD brain [212, 214].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
AEP activity was initially reported to be increased in aged mouse and human AD brain, and tau-368 was shown to increase during aging and in AD brain.
“AEP activity was initially reported to be increased in aged mouse and human AD brain, and tau-368 was shown to increase during aging and in AD brain [212].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
Truncated tau 1-368 (tau-368) generated by AEP cleavage exhibits impaired enhancement in microtubule assembly, and shows increased propensity to form PHFs in vitro.
“The truncated tau 1–368 (tau-368) isoform generated by AEP cleavage exhibits impaired enhancement in microtubule assembly, and shows increased propensity to form PHFs in vitro.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
AEP likely plays a role in regulating tau degradation, rather than enhancing tau aggregation.
“It is therefore likely that AEP plays a role in regulating tau degradation, rather than enhancing tau aggregation [212, 213, 215].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [212]
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Xiong, J., Zhang, Z., & Ye, K. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01025-w · Cited by 37 · see citing works
Self-citationTripathy, R. K., Frohock, Z., Wang, H., Cary, G. A., Keegan, S., Carter, G. W., & Li, Y. (2025) · npj Systems Biology and Applications · doi:10.1038/s41540-025-00519-9 · Cited by 36 · see citing works
The metamorphic nature of the Tau protein: dynamic flexibility comes at a cost
Sabbagh, J. J., & Dickey, C. A. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00003 · Cited by 31 · see citing works
“It was also recently discovered that tau can be cleaved by asparagine endopeptidase, a lysosomal cysteine protease, which (1) abrogates the ability of tau to stabilize microtubules, (2) induces aggregation, and (3) enhances neurodegeneration (Zhang et al., 2014).”
BackgroundLobine, D., Sadeer, N., Jugreet, S., Suroowan, S., Keenoo, B. S., Imran, M., Venugopala, K. N., Ibrahim, F. M., Zengin, G., & Mahomoodally, M. F. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210412095251 · Cited by 32 · see citing works
Chen, G., Ahn, E. H., Kang, S. S., Xia, Y., Liu, X., Zhang, Z., & Ye, K. (2022) · Advanced Science · doi:10.1002/advs.202103396 · Cited by 28 · see citing works
Self-citationAsparagine endopeptidase cleaves tau at N167 after uptake into microglia
Behrendt, A., Bichmann, M., Ercan-Herbst, E., Haberkant, P., Schöndorf, D. C., Wolf, M., Fahim, S. A., Murolo, E., & Ehrnhoefer, D. E. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104518 · Cited by 26 · see citing works
Chen, R., Pan, C., Mao, X., Zhang, Y., Chen, G., Xu, M., Nivar, J., Tao, Y., Cao, H., & Li, J. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.134972 · Cited by 7 · see citing works
Retracted
- Authors
- Zhang, Z., Song, M., Liu, X., Kang, S. S., Kwon, I.-S., Duong, D. M., Seyfried, N. T., Hu, W. T., Liu, Z., Wang, J.-Z., Cheng, L., Sun, Y. E., Yu, S. P., Levey, A. I., & Ye, K.
- Affiliations
- Emory University (US)
- Chinese Academy of Sciences (CN)
- Huazhong University of Science and Technology (CN)
- Tongji University (CN)
- Corresponding author
- Cheng, Liming
- Ye, Keqiang
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-10-19
- Volume
- 20
- Issue
- 11
- Pages
- 1254-1262
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4224595
- OpenAlex
- W2026077861
- Cited by
- 494
- References
- 47
- Citations by year
- 2026: 29 · 2025: 51 · 2024: 45 · 2023: 65 · 2022: 51 · 2021: 47 · 2020: 44 · 2019: 42 · 2018: 44 · 2017: 27 · 2016: 26 · 2015: 20 · 2014: 3
- FWCI
- 16.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Emory University
- National Institute on Aging (P01AG014449, K23AG042856, R01AG043375, P50AG025688)
- National Institute of Neurological Disorders and Stroke (R01NS060680, R01NS045627)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau cleavage, asparaginyl endopeptidase, Alzheimer's disease, neurofibrillary tangles, tau truncation, tau hyperphosphorylation, tau aggregation, microtubule assembly, neurodegeneration, aging, synaptic loss, cognitive impairment, lysosomal cysteine proteases
- MeSH terms
- Asparaginyl Endopeptidase, Aged, Aging, Alzheimer Disease, Amino Acid Sequence, Animals, Asparagine, Brain, Calpain, Cognition, Cysteine Endopeptidases, Humans, Memory Disorders, Mice, Transgenic, Molecular Sequence Data, Neurotoxins, Phosphorylation, Solubility, Synapses, Up-Regulation, Neurofibrillary Tangles, tau Proteins, Protein Structure, Tertiary, Caspases, Gene Knockout Techniques, HEK293 Cells
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