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Behav Brain Res. 2008 Aug 22;191(2):246-55. doi: 10.1016/j.bbr.2008.03.035. Epub 2008 Apr 8.

Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664.

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1
Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA. vgalvan@buckinstitute.org

Abstract

The deficits of Alzheimer's disease (AD) are believed to result, at least in part, from neurotoxicity of beta-amyloid (Abeta), a set of 38-43 amino acid fragments derived from the beta-amyloid precursor protein (APP). In addition, APP generates the APP-C31 and Jcasp toxic fragments intracellularly by cleavage at Asp664. We reported that mutation of Asp664 to Ala in a FAD-human APP transgene prevented AD-like deficits but did not affect Abeta production or deposition in PDAPP mice, arguing that D664A plays a crucial role in the generation of AD-like deficits. Whether D664A simply delays or completely prevents AD-like deficits, however, remained undefined. To address this question, we performed behavioral studies longitudinally on a pretrained mouse cohort at 9 and 13 months (mo) of age. While behavioral deficits were present in PDAPP mice, performance of Tg PDAPP(D664A) mice was not significantly different from non-Tg littermates' across all ages tested. Moreover, aberrant patterns in non-cognitive components of behavior in PDAPP mice were ameliorated in PDAPP(D664A) animals as well. A trend towards poorer retention at 9 mo and poorer learning at 13 mo that did not reach statistical significance was observed in PDAPP(D664A) mice. These results support and extend recent studies showing that cleavage of APP at Asp664 (or protein-protein interactions dependent on Asp664) is a crucial event in the generation of AD-like deficits in PDAPP mice. Our results thus further demonstrate that the D664A mutation either completely precludes, or markedly delays (beyond 13 mo) the appearance of AD-like deficits in this mouse model of AD.

PMID:
18485495
PMCID:
PMC2757410
DOI:
10.1016/j.bbr.2008.03.035
[Indexed for MEDLINE]
Free PMC Article
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