BACE1 gene deletion:: Impact on behavioral function in a model of Alzheimer's disease

被引：82

作者：

Kobayashi, Dione ^{[1
]}

Zeller, Michelle ^{[2
]}

Cole, Tracy ^{[2
]}

Buttini, Manuel ^{[2
]}

McConlogue, Lisa ^{[2
]}

Sinha, Sukanto ^{[3
]}

Freedman, Stephen ^{[4
]}

Morris, Richard G. M. ^{[5
]}

Chen, Karen S. ^{[6
]}

机构：

[1] Rinat Neurosci, San Francisco, CA 94080 USA

[2] Elan Pharmaceut, San Francisco, CA 94080 USA

[3] Activesite Pharmaceut, Berkeley, CA 94710 USA

[4] SBF Consulting LLC, San Francisco, CA 94105 USA

[5] Univ Edinburgh, Div Neurosci, Cognit Neurosci Lab, Edinburgh EH8 9JZ, Midlothian, Scotland

[6] Roche Pharmaceut, Palo Alto, CA 94301 USA

来源：

NEUROBIOLOGY OF AGING | 2008年 / 29卷 / 06期

基金：

英国医学研究理事会;

关键词：

A beta; Alzheimer's disease; amyloid; APP; BACE1; memory; PDAPP; seizure; sensorimotor; serial water maze;

D O I：

10.1016/j.neurobiolaging.2007.01.002

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

Accumulation of cerebral amyloid-beta (A beta) 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 P-site aspartyl cleaving enzyme (BACE1) enzyme responsible for the first proteolytic cleavage that ultimately generates A beta 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 hA beta accumulation, BACE1(-1-) 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 A beta is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in "normal" learning, memory and sensorimotor processes. (C) 2007 Elsevier Inc. All rights reserved.

引用

页码：861 / 873

页数：13

共 57 条

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