Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664.
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.
Galvan
Veronica
V
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Gorostiza
Olivia F
OF
Banwait
Surita
S
Ataie
Marina
M
Logvinova
Anna V
AV
Sitaraman
Sandhya
S
Carlson
Elaine
E
Sagi
Sarah A
SA
Chevallier
Nathalie
N
Jin
Kunlin
K
Greenberg
David A
DA
Bredesen
Dale E
DE
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D049109:Cell Proliferation; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology; D017354:Point Mutation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D001224:Aspartic Acid