Lack of Pathology in a Triple Transgenic Mouse Model of Alzheimer’s Disease after Overexpression of the Anti-Apoptotic Protein Bcl-2
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Alzheimer's disease (AD) is characterized by the accumulation of plaques containing beta-amyloid (Abeta) and neurofibrillary tangles (NFTs) consisting of modified tau. Although Abeta deposition is thought to precede the formation of NFTs in AD, the molecular steps connecting these two pathologies is not known. Previous studies have suggested that caspase activation plays an important role in promoting the pathology associated with AD. To further understand the contribution of caspases in disease progression, a triple transgenic Alzheimer's mouse model overexpressing the anti-apoptotic protein Bcl-2 was generated. Here we show that overexpression of Bcl-2 limited caspase-9 activation and reduced the caspase cleavage of tau. Moreover, overexpression of Bcl-2 attenuated the processing of APP (amyloid precursor protein) and tau and reduced the number of NFTs and extracellular deposits of Abeta associated with these animals. In addition, overexpression of Bcl-2 in 3xTg-AD mice improved place recognition memory. These findings suggest that the activation of apoptotic pathways may be an early event in AD and contributes to the pathological processes that promote the disease mechanisms underlying AD.
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Executioner caspases 3 and 7 may contribute to tau pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment.
“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 Rohn et al., 2008
The Results section (page unavailable) reports caspase-cleaved tau at Asp421 in the mouse model, and the Discussion links caspase cleavage of tau to NFT pathology. The paper identifies caspase-3 as an executioner caspase, but the passages do not identify caspase-7 as a tau-cleaving enzyme or describe the resulting fragment as cytotoxic Δtau. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn 3xTg mice, quantitative analysis of CA1 neuron numbers revealed a lack of neuron loss in this brain region during aging.
“Interestingly, staining with Fluoro Jade C, a marker for degenerating neurons, did not reveal evidence for neurodegeneration [109] and a quantitative analysis of CA1 neuron numbers revealed a lack of neuron loss in this brain region in 3xTg mice during aging [110].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [109]
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- Authors
- Rohn, T. T., Vyas, V., Hernandez-Estrada, T., Nichol, K. E., Christie, L.-A., & Head, E.
- Affiliations
- Boise State University (US)
- University of California, Irvine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-03-19
- Volume
- 28
- Issue
- 12
- Pages
- 3051-3059
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6670712
- OpenAlex
- W2086662417
- Cited by
- 146
- References
- 43
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 9 · 2017: 2 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 7 · 2012: 8
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ScholarWorks (Boise State University) (submittedVersion)
- Funders
- American Health Assistance Foundation
- National Institutes of Health (AG16573)
- Directorate for Biological Sciences
- University of California, Irvine (P20RR016454, P50 AG16573)
- National Research Council Canada
- National Institute on Aging (P50 AG 16573, P50AG016573)
- National Center for Research Resources (P50 AG16573, P20RR016454)
- 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
- Alzheimer's disease, Bcl-2, caspase-9, apoptosis, neurofibrillary tangles, amyloid plaques, tau cleavage, APP processing, 3xTg-AD mice, triple transgenic mouse model
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Behavior, Animal, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Fluoresceins, Gene Expression Regulation, Humans, Memory, Mice, Transgenic, Organic Chemicals, Amyloid beta-Protein Precursor, tau Proteins, Proto-Oncogene Proteins c-bcl-2, Caspases, Infarction, Middle Cerebral Artery, Mice, Presenilin-1
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