Many Neuronal and Behavioral Impairments in Transgenic Mouse Models of Alzheimer's Disease Are Independent of Caspase Cleavage of the Amyloid Precursor Protein
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Previous studies suggested that cleavage of the amyloid precursor protein (APP) at aspartate residue 664 by caspases may play a key role in the pathogenesis of Alzheimer's disease. Mutation of this site (D664A) prevents caspase cleavage and the generation of the C-terminal APP fragments C31 and Jcasp, which have been proposed to mediate amyloid-β (Aβ) neurotoxicity. Here we compared human APP transgenic mice with (B254) and without (J20) the D664A mutation in a battery of tests. Before Aβ deposition, hAPP–B254 and hAPP–J20 mice had comparable hippocampal levels of Aβ 1-42 . At 2–3 or 5–7 months of age, hAPP–B254 and hAPP–J20 mice had similar abnormalities relative to nontransgenic mice in spatial and nonspatial learning and memory, elevated plus maze performance, electrophysiological measures of synaptic transmission and plasticity, and levels of synaptic activity-related proteins. Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities.
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C1q elevation was region-specific, particularly in hippocampus and frontal cortex.
“C1q elevation was region-specific, particularly in hippocampus and frontal cortex, two regions vulnerable to synapse loss (14) (Fig. 1B and fig. S2A).”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [14]
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References 55 · Cited by 146
- Authors
- Harris, J. A., Devidze, N., Halabisky, B., Lo, I., Thwin, M. T., Yu, G.-Q., Bredesen, D. E., Masliah, E., & Mucke, L.
- Affiliations
- University of California, San Francisco (US)
- Gladstone Institutes (US)
- Buck Institute for Research on Aging (US)
- University of California San Diego (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-06
- Volume
- 30
- Issue
- 1
- Pages
- 372-381
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3064502
- OpenAlex
- W2078459727
- Cited by
- 146
- References
- 55
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 13 · 2016: 7 · 2015: 9 · 2014: 10 · 2013: 8 · 2012: 12
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG011385)
- National Institute on Aging (AG011385, R37AG011385, R01AG011385)
- National Institute of Neurological Disorders and Stroke (R01NS041787, NS041787)
- 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, amyloid precursor protein, caspase cleavage, APP transgenic mice, amyloid-beta, learning and memory, spatial learning, synaptic transmission, synaptic plasticity, hippocampus, behavioral impairment
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Hydrolysis, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neurons, Psychomotor Performance, Amyloid beta-Protein Precursor, Caspases, Mice
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