Many Neuronal and Behavioral Impairments in Transgenic Mouse Models of Alzheimer's Disease Are Independent of Caspase Cleavage of the Amyloid Precursor Protein

Overview

Journal J Neurosci

Specialty Neurology

Date 2010 Jan 8

PMID 20053918

Citations 87

Authors

Julie A Harris

Nino Devidze

Brian Halabisky

Iris Lo

Myo T Thwin

Gui-Qiu Yu

Dale E Bredesen

Eliezer Masliah

Lennart Mucke

Affiliations

Soon will be listed here.

Abstract

Previous studies suggested that cleavage of the amyloid precursor protein (APP) at aspartate residue 664 by caspases may play a key role in the pathogenesis of Alzheimer's disease. Mutation of this site (D664A) prevents caspase cleavage and the generation of the C-terminal APP fragments C31 and Jcasp, which have been proposed to mediate amyloid-beta (Abeta) neurotoxicity. Here we compared human APP transgenic mice with (B254) and without (J20) the D664A mutation in a battery of tests. Before Abeta deposition, hAPP-B254 and hAPP-J20 mice had comparable hippocampal levels of Abeta(1-42). At 2-3 or 5-7 months of age, hAPP-B254 and hAPP-J20 mice had similar abnormalities relative to nontransgenic mice in spatial and nonspatial learning and memory, elevated plus maze performance, electrophysiological measures of synaptic transmission and plasticity, and levels of synaptic activity-related proteins. Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities.

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