期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 38, 页码 32957-32967出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M507016200
关键词
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资金
- NIA NIH HHS [AG022074, AG10869, AG18840, AG5131] Funding Source: Medline
Amyloid-beta peptides (A beta) are widely presumed to play a causal role in Alzheimer disease. Release of A beta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human ( h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and A beta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human A beta. Thus, inhibiting BACE1 may block not only A beta-dependent but also A beta-independent pathogenic mechanisms.
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