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Active Caspase-6 and Caspase-6-Cleaved Tau in Neuropil Threads, Neuritic Plaques, and Neurofibrillary Tangles of Alzheimer's Disease
Open accessAbstract
Previously, we have shown that caspase-6 but not caspase-3 is activated by serum deprivation and induces a protracted cell death in primary cultures of human neurons (LeBlanc AC, Liu H, Goodyer C, Bergeron C, Hammond J: Caspase-6 role in apoptosis of human neurons, amyloidogenesis and Alzheimer's disease. J Biol Chem 1999, 274:23426-23436 and Zhang Y, Goodyer C, LeBlanc A: Selective and protracted apoptosis in human primary neurons microinjected with active caspase-3, -6, -7, and -8. J Neurosci 2000, 20:8384-8389). Here, we show with neoepitope antibodies that the p20 subunit of active caspase-6 increases twofold to threefold in the affected temporal and frontal cortex but not in the unaffected cerebellum of Alzheimer's disease brains and is present in neurofibrillary tangles, neuropil threads, and the neuritic plaques. Furthermore, a neoepitope antibody to caspase-6-cleaved Tau strongly detects intracellular tangles, extracellular tangles, pretangles, neuropil threads, and neuritic plaques. Immunoreactivity with both antibodies in pretangles indicates that the caspase-6 is active early in the pathogenesis of Alzheimer's disease. In contrast to the nuclear and cytosolic localization of active caspase-6 in apoptotic neurons of fetal and adult ischemic brains, the active caspase-6 in Alzheimer's disease brains is sequestered into the tangles or neurites. The localization of active caspase-6 may strongly jeopardize the structural integrity of the neuronal cytoskeletal system leading to inescapable neuronal dysfunction and eventual cell death in Alzheimer's disease neurons. Our results suggest that active caspase-6 is strongly implicated in human neuronal degeneration and apoptosis.
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“Active caspase-6 and tau-402 were observed in NFTs and neuritic plaques in AD brain [193].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [193]
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In the citing paper
“Mice expressing the mutant variant exhibit well characterized age-dependant increases in neuronal tau pathology within cell bodies, dendrites and axons mimicking pathology observed in AD 23.”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [23]
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“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 [193]
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 [193]
In the citing paper
“Tau can be cleaved by caspase-6 at Asp13 (tau-13) and Asp402 (tau-402) [193, 198].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [193]
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Cites
Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice
Kuida, K., Zheng, T. S., Na, S., Kuan, C.-Y., Yang, D., Karasuyama, H., RAKIC, P. T., & Flavell, R. A. (1996) · Nature · doi:10.1038/384368a0 · Cited by 1,881
A Unified Model for Apical Caspase Activation
Boatright, K. M., Renatus, M., Scott, F. L., Sperandio, S., Shin, H., Pedersen, I. M., Ricci, J., Edris, W. A., Sutherlin, D. P., Green, D. R., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00051-0 · Cited by 986
Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease
Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1630428100 · Cited by 831
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Self-citationEffects of environmental enrichment on gene expression in the brain
Rampon, C., Jiang, C. H., Dong, H., Tang, Y., Lockhart, D. J., Schultz, P. G., Tsien, J. Z., & Hu, Y. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.23.12880 · Cited by 614
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Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis
Byun, Y., Chen, F., Chang, R., Trivedi, M., Green, K. J., & Cryns, V. L. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400840 · Cited by 339
The effects of aging on gene expression in the hypothalamus and cortex of mice
Jiang, C. H., Tsien, J. Z., Schultz, P. G., & Hu, Y. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1930 · Cited by 318
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Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M. (2009) · Nature · doi:10.1038/nature07767 · Cited by 992
RetractedCaspases in Cell Death, Inflammation, and Pyroptosis
Kesavardhana, S., Malireddi, R. K. S., & Kanneganti, T. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-073119-095439 · Cited by 954
Post-translational modifications of tau protein: Implications for Alzheimer's disease
Martin, L., Latypova, X., & Terro, F. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2010.12.023 · Cited by 683
Metadata
- Authors
- Guo, H., Albrecht, S., Bourdeau, M., Petzke, T., Bergeron, C., & LeBlanc, A. C.
- Affiliations
- Jewish General Hospital (CA)
- University of Toronto (CA)
- Corresponding author
- LeBlanc, Andrea C.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 165
- Issue
- 2
- Pages
- 523-531
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1618555
- OpenAlex
- W1997426613
- Cited by
- 287
- References
- 32
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 21 · 2020: 11 · 2019: 16 · 2018: 13 · 2017: 10 · 2016: 10 · 2015: 10 · 2014: 11 · 2013: 19 · 2012: 19
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- National Institutes of Health (1r03mh040965-01)
- National Institute of Neurological Disorders and Stroke (NS/MH40965)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- caspase-6, Alzheimer's disease, neurofibrillary tangles, neuropil threads, neuritic plaques, neuronal apoptosis, tau cleavage, neurodegeneration, caspase-3
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Cell Nucleus, Cerebellum, Cerebral Cortex, Cytosol, Humans, Middle Aged, Neurofibrillary Tangles, tau Proteins, Apoptosis, Neuropil Threads, Caspases, Caspase 6, Plaque, Amyloid
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