title: BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease.
abstract: Accumulation of cerebral amyloid-beta (Abeta) has been implicated as a putative causal factor in the development of Alzheimer's disease (AD). Transgenic mice like the PDAPP line overexpress human mutant Amyloid Precursor Protein (hAPP) and recapitulate many features of AD, including amyloid neuropathology and cognitive deficits. Inhibition of the beta-site aspartyl cleaving enzyme (BACE1) enzyme responsible for the first proteolytic cleavage that ultimately generates Abeta has been proposed as a strategy for AD therapy. To assess the theoretical repercussions of beta-secretase activity reduction in an in vivo model of AD, BACE1(-/-) mice bred to the PDAPP line were examined in a series of behavioral tasks. Although BACE1 gene ablation abolished hAbeta accumulation, BACE1(-/-) mice had unexpected sensorimotor impairments, spatial memory deficits, and displayed seizures, phenotypes which were severe on the PDAPP background. These results suggest that while excess Abeta is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in "normal" learning, memory and sensorimotor processes.
authors.affiliation: Rinat Neurosciences, 230 East Grand Avenue, South San Francisco, CA 94080, USA. dkobayashi@rinatneuro.com
authors.forename: Dione
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Michelle
authors.initials: M
authors.lastname: Zeller
authors.forename: Tracy
authors.initials: T
authors.lastname: Cole
authors.forename: Manuel
authors.initials: M
authors.lastname: Buttini
authors.forename: Lisa
authors.initials: L
authors.lastname: McConlogue
authors.forename: Sukanto
authors.initials: S
authors.lastname: Sinha
authors.forename: Stephen
authors.initials: S
authors.lastname: Freedman
authors.forename: Richard G M
authors.initials: RG
authors.lastname: Morris
authors.forename: Karen S
authors.initials: KS
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001522:Behavior, Animal; D017353:Gene Deletion; D001523:Mental Disorders / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse