The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
Open accessAbstract
Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ1–42 and is induced by Aβ1–42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.
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In the citing paper
“This is consistent with the observation that C-terminal truncated forms of Tau show increased polymerization capacity in vitro and are associated with NFTs formation in the brain of AD patients (Gamblin et al., 2003; Rissman et al., 2004).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Rissman et al., 2004
In the citing paper
“Δtau levels were below the detectable level in our 7-month-old, untreated 3xTg-AD mice”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Rissman et al., 2004
In the citing paper
“Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Rissman et al., 2004
In the citing paper
“only caspase-2, 3 and 6 cleaved tau products have been linked to AD [190–193].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Although tau can be cleaved by caspase-1, 2, 3, 6 and 7 in vitro”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Tau-421 colocalizes with NFTs in human AD brain, and correlates with NFT formation and cognitive impairment in aged mice [191, 192, 194].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Elevated levels of caspase-3 and tau-421 have been observed in AD, as well as PSP [130, 191, 192].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
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Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics
Kerr, J. F. R., Wyllie, A. H., & Currie, A. R. (1972) · British Journal of Cancer · doi:10.1038/bjc.1972.33 · Cited by 15,673
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Mild Cognitive Impairment: Clinical Characterization and Outcome
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999) · Archives of Neurology · doi:10.1001/archneur.56.3.303 · Cited by 8,980
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126
Self-citationLee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480
Buée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,142
Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
Grundke, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., & Wisniewski, H. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38495-8 · Cited by 1,780
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., et al. (2001) · Science · doi:10.1126/science.1058189 · Cited by 1,611
Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils
Götz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001) · Science · doi:10.1126/science.1062097 · Cited by 1,526
Flagged first, then by citations
Research works printed but not linked: 1
- Yang, 1998, Am. J. Pathol., 152, 379
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Sorted by citations
Items 501–544 of 544
Rohn, T. T., & Head, E. (2008)
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Farmácia, F. D. (2007)
Croft, C. L. (2016) · Research Portal (King's College London)
García‐Sierra, F. (2016) · Journal of Medical & Surgical Pathology · doi:10.4172/2472-4971.1000121
Molecular Aspects of Concussion and Chronic Traumatic Encephalopathy
Farooqui, A. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813596-9.00008-0
Envolvimento da NADPH oxidase 2 na neurodegeneração induzida por estreptozotocina.
Ravelli, K. G. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2018.tde-22022018-104337
Crunfli, F. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2018.tde-14032018-110624
Diyet Yağlarının Alzheimer Hastalığı Patolojisi Üzerine Potansiyel Koruyucu Etkileri
Karagöz, M. F., & Tek, N. A. (2018) · Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi · doi:10.22312/sdusbed.412464
Identifying stage-specific markers of Alzheimer's disease using quantitative proteomics
Yagensky, O. (2018) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7052
Mechanistic Insight into Tau Fibril Cross-Seeding Barriers: Structural Order and Disorder
Weismiller, H. A. (2019) · Digital Commons - DU (University of Denver)
Regulation of apoptosis at the point of cytochrome c in disease models
Huang, Y. Y. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/311m-cp59
Tau proteolysis mechanisms and relevance for tauopathies
Quinn, J. P. (2019) · Research Explorer (The University of Manchester)
Activation of glycogen synthase kinase 3β promotes the intermolecular association of tau.
Chun, W., & Johnson, G. V. W. (2007) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)58726-7
Jadhav, V. (2021) · IUScholarWorks (Indiana University) · doi:10.7912/c2/2086
Animal Models in Neuro Ophthalmology
Normando, E. M., & Cordeiro, M. F. (2020) · Springer eBooks · doi:10.1007/978-3-030-26269-3_19
Deep trans-omic network fusion reveals altered synaptic network in Alzheimer’s DiseasePreprint
Xie, L., Raj, Y., Varathan, P., He, B., Nho, K. T., Risacher, S. L., Salama, P., Saykin, A. J., & Yan, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.02.490336
Axelsen, T. M., Høgh, P., Bihlet, A. R., Karsdal, M. A., Henriksen, K., Hasselbalch, S. G., & Simonsen, A. H. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.43
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Bisi, N., Pinzi, L., & Rastelli, G. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104352
Animal Models in Neuro Ophthalmology
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Self-citationYang, W., Yu, Z., Wang, W., & Yan, S. (2025) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2025.29
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García‐González, L. (2020) · theses.fr (ABES) · doi:10.70675/a04672c0z1f4az472ezbcd5zbea446eac50c
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Canet, G. (2020) · theses.fr (ABES) · doi:10.70675/c46cedbczd8bbz4a8eza301z82de5785048c
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Barbereau, C. (2020) · theses.fr (ABES) · doi:10.70675/dfe1802ez70f2z4da6zb3e5z63d1de7a429c
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Derisbourg, M. J. (2015) · theses.fr (ABES) · doi:10.70675/ef5f45b0zf4e8z433fz9beaz8d2cc6de65bc
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Danis, C. (2018) · theses.fr (ABES) · doi:10.70675/c783a062zb57bz4024z85d0z509baaed8a1b
Delangre, E. (2021) · theses.fr (ABES) · doi:10.70675/622d48edz59dcz427ez85c9z9da5f8129e84
Neuroinflammation- molecular target based therapeutic approach
Paul, D. (2026) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2026.04.006
The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer’s disease
Singh, A. K., Supraja, M. R., Amal, P. S., Krishnamoorthi, S., Iyaswamy, A., & Durairajan, S. S. K. (2026) · International review of neurobiology · doi:10.1016/bs.irn.2026.06.002
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Mukherjee, M., Dhara, S., Jana, A., & Roy, T. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898815646126010005
Goate, A., Romero‐Molina, C., Gomez‐Gutierrez, R., See, W. Y., Patel, T., Davtyan, H., Ma, J., Xu, Q. A., Sewell, M., Allton, K. L., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10216155/v1
Self-citationSeo, S., Lee, J., Cho, E., & Shin, E. (2026) · Parasite Immunology · doi:10.1111/pim.70096
Metadata
- Authors
- Rissman, R. A., Poon, W. W., Blurton-Jones, M., Oddo, S., Torp, R., Vitek, M. P., LaFerla, F. M., Rohn, T. T., & Cotman, C. W.
- Affiliations
- University of California, Irvine (US)
- Duke Medical Center (US)
- Boise State University (US)
- Corresponding author
- Cotman, Carl W.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-07-01
- Volume
- 114
- Issue
- 1
- Pages
- 121-130
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC437967
- OpenAlex
- W1989856924
- Cited by
- 543
- References
- 82
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 20 · 2023: 20 · 2022: 20 · 2021: 23 · 2020: 32 · 2019: 28 · 2018: 33 · 2017: 24 · 2016: 30 · 2015: 26 · 2014: 19 · 2013: 27 · 2012: 30
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ScholarWorks (Boise State University) (submittedVersion)
- Funders
- National Institutes of Health (1r03ag019386-01, AG016573, AG000096, AG000538)
- National Institute on Aging (P01AG000538, AG19386, AG19780, AG-000538, AG17968, AG000096, R01AG017968, P50AG016573, F32AG023433, AG023433, R01AG019780, T32AG000096)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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, caspase activation, neurofibrillary tangles, Alzheimer's disease, amyloid-beta, glycogen synthase kinase-3β, tau phosphorylation, PHF1, cognitive decline, mild cognitive impairment, traumatic brain injury, triple transgenic mouse model
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Proteins, Mice, Transgenic, Phosphorylation, Reference Values, Neurofibrillary Tangles, tau Proteins, Pyramidal Cells, Mice, Knockout, Caspases, Mice, Presenilin-1
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