BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

NEUROBIOLOGY OF DISEASE

卷:26

Article

Ohno, Masuo ; Cole, Sarah L. ; Yasvoina, Marina ; Zhao, Jie ; Citron, Martin ; Berry, Robert ; Disterhoft, John F. ; Vassar, Robert

关键词: Alzheimer's disease;    beta-amyloid (A beta);    beta-secretase;    BACE1 knockout;    Tg6799;    gliosis;    cognitive impairment;    spontaneous alternation;    Y-maze;   

DOI  :  10.1016/j.nbd.2006.12.008

来源: Elsevier

【 摘 要 】

Evidence suggests that beta-amyloid (A beta) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between A beta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates A beta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that A beta ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD. (c) 2006 Elsevier Inc. All rights reserved.

【 授权许可】

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