Active Caspase-6 and Caspase-6-Cleaved Tau in Neuropil Threads, Neuritic Plaques, and Neurofibrillary Tangles of Alzheimer's Disease
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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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p301L tau mice exhibit well-characterized age-dependent increases in neuronal tau pathology within cell bodies, dendrites and axons, mimicking pathology observed in AD.
“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]
The Tissue Collection and Characterization section describes human AD and control brains, and Results and Discussion reports tau pathology in those brains. Our copy does not address P301L tau mice or age-dependent changes in their cell bodies, dendrites, and axons (searched: P301L tau transgenic mice; mutant tau mice age-dependent pathology). (LLM, conf=0.77)
Experimental — accuracy not yet measuredOnly caspase-2, 3 and 6 cleaved tau products have been linked to AD.
“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]
Tau can be cleaved by caspase-1, 2, 3, 6 and 7 in vitro.
“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]
Tau can be cleaved by caspase-6 at Asp13 (tau-13) and Asp402 (tau-402).
“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]
Active caspase-6 and tau-402 were observed in NFTs and neuritic plaques in AD brain.
“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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Self-citation
- 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
- Health Sciences › Medicine › Physiology › 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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