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

Veronica Galvan, Olivia F. Gorostiza, Surita Banwait, Marina Ataie, Anna V. Logvinova, Sandhya Sitaraman, Elaine Carlson, Sarah A. Sagi, Nathalie Chevallier, Kunin Jin, David A. Greenberg, Dale E. Bredesen

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200 Scopus citations

Abstract

The deficits characteristic of Alzheimer's disease (AD) are believed to result at least in part, from the neurotoxic effects of β-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from β-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 β-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.

Original languageEnglish
Pages (from-to)7130-7135
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number18
DOIs
StatePublished - 2 May 2006

Keywords

  • Caspase
  • Memory
  • Neurodegeneration
  • β-amyloid precursor protein intracytoplasmic domain
  • β-amyloid precursor protein-c31

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    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. (2006). Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proceedings of the National Academy of Sciences of the United States of America, 103(18), 7130-7135. https://doi.org/10.1073/pnas.0509695103