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Cited by 239Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664

Galvan, Veronica, Gorostiza, Olivia F., Banwait, Surita, Ataie, Marina, Logvinova, Anna V., Sitaraman, Sandhya, Carlson, Elaine, Sagi, Sarah A. +4 more·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0509695103
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Abstract

The deficits characteristic of Alzheimer's disease (AD) are believed to result, at least in part, from the neurotoxic effects of beta-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from beta-amyloid precursor protein (APP). APP also is cleaved intracytoplasmically at Asp-664 to generate a second cytotoxic peptide, APP-C31, but whether this C-terminal processing of APP plays a role in the pathogenesis of AD is unknown. Therefore, we compared elements of the Alzheimer's phenotype in transgenic mice modeling AD with vs. without a functional Asp-664 caspase cleavage site. Surprisingly, whereas beta-amyloid production and plaque formation were unaltered, synaptic loss, astrogliosis, dentate gyral atrophy, increased neuronal precursor proliferation, and behavioral abnormalities were completely prevented by a mutation at Asp-664. These results suggest that Asp-664 plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP transgenic mice, possibly as a cleavage site or via protein-protein interactions.

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Crossref · 10.1073/pnas.0509695103

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  • Transgenic mice overexpressing APP which lack a caspase cleavage site in the C-terminal cytoplasmic region of APP generate large amounts of Ab peptides, but do not exhibit the significant cellular, synaptic and behavioral changes seen in matched transgenic mice producing comparable levels of Ab, but in which the caspase cleavage site is intact.

    “These transgenic mice generate large amounts of Ab peptides, but they do not exhibit the significant cellular, synaptic and behavioral changes seen in matched transgenic mice producing comparable levels of Ab, but in which the caspase cleavage site is intact(63).”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [63]

  • Our data are consistent with a recent report about transgenic mice overexpressing APP which lack a caspase cleavage site in the C-terminal cytoplasmic region of APP.

    “Finally, our data are consistent with a recent report about transgenic mice overexpressing APP which lack a caspase cleavage site in the C-terminal cytoplasmic region of APP.”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [63]

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Authors
Galvan, V., Gorostiza, O. F., Banwait, S., Ataie, M., Logvinova, A. V., Sitaraman, S., Carlson, E., Sagi, S. A., Chevallier, N., Jin, K., Greenberg, D. A., & Bredesen, D. E.
Affiliations
  • *Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945;
  • Buck Institute for Research on Aging (US)
  • Massachusetts Institute of Technology (US)
  • University of California, San Francisco (US)
  • University of California San Diego (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-05-02
Volume
103
Issue
18
Pages
7130-7135
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0509695103
OpenAlex
W2076184221
Cited by
239
References
4
Citations by year
2026: 2 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 10 · 2016: 6 · 2015: 4 · 2014: 9 · 2013: 19 · 2012: 18
FWCI
17.72
Type
journal article
Language
en
Update notices
correction (2007-04-17)
Open access
closed
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • Buck Institute for Research on Aging
  • John Douglas French Alzheimer's Foundation
  • National Institutes of Health (AG05131)
  • University of California, San Francisco
  • National Institute on Aging (AG05131, P50AG005131)
  • National Institute of Neurological Disorders and Stroke (R01NS045093, NS-45093)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, APP transgenic mice, caspase cleavage sites, APP processing, amyloid-beta, amyloid plaques, synaptic loss, astrocyte activation, neural progenitor proliferation, behavioral abnormalities, neuroprotection
MeSH terms
Alzheimer Disease, Animals, Aspartic Acid, Astrocytes, Behavior, Animal, Cognition Disorders, Hippocampus, Humans, Mice, Transgenic, Neurons, Stem Cells, Amyloid beta-Protein Precursor, Point Mutation, Maze Learning, Cell Proliferation, Mice

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