TY - JOUR
T1 - Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664
AU - Galvan, Veronica
AU - Gorostiza, Olivia F.
AU - Banwait, Surita
AU - Ataie, Marina
AU - Logvinova, Anna V.
AU - Sitaraman, Sandhya
AU - Carlson, Elaine
AU - Sagi, Sarah A.
AU - Chevallier, Nathalie
AU - Jin, Kunin
AU - Greenberg, David A.
AU - Bredesen, Dale E.
PY - 2006/5/2
Y1 - 2006/5/2
N2 - 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.
AB - 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.
KW - Caspase
KW - Memory
KW - Neurodegeneration
KW - β-amyloid precursor protein intracytoplasmic domain
KW - β-amyloid precursor protein-c31
UR - http://www.scopus.com/inward/record.url?scp=33646480747&partnerID=8YFLogxK
U2 - 10.1073/pnas.0509695103
DO - 10.1073/pnas.0509695103
M3 - Article
C2 - 16641106
AN - SCOPUS:33646480747
SN - 0027-8424
VL - 103
SP - 7130
EP - 7135
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -