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Proc Natl Acad Sci U S A. 2006 May 2;103(18):7130-5. Epub 2006 Apr 25.

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

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  • 1Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6876.

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.

PMID:
16641106
[PubMed - indexed for MEDLINE]
PMCID:
PMC1459029
Free PMC Article
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