title: Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664.
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.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
authors.forename: Olivia F
authors.initials: OF
authors.lastname: Gorostiza
authors.forename: Surita
authors.initials: S
authors.lastname: Banwait
authors.forename: Marina
authors.initials: M
authors.lastname: Ataie
authors.forename: Anna V
authors.initials: AV
authors.lastname: Logvinova
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sitaraman
authors.forename: Elaine
authors.initials: E
authors.lastname: Carlson
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sagi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chevallier
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: 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
chemical_list: D016564:Amyloid beta-Protein Precursor; D001224:Aspartic Acid