期刊
NEUROCHEMISTRY INTERNATIONAL
卷 52, 期 4-5, 页码 683-687出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2007.08.017
关键词
caspase-4; caspase-3; caspase-9; familial AD-linked presenilin-1 mutation; ER stress; mitochondria; Alzheimer's disease
In the previous reports, we showed that the familial Alzheimer's disease (AD)-linked presenilin-1 (PS1) mutation induced the fragility to the endoplasmic reticulum (ER) stress and that caspase-4 mediates ER stress-induced- and beta-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. In this report, we studied the activation of caspase-4 in the familial AD-linked PS I mutation (Delta E9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (Delta E9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. Thus, caspase-4 activates downstream caspases independently of mitochondrial apoptotic signaling and this might contribute to the pathogenesis of AD. To sum up our data, the familial AD-linked PS1 mutation accelerates the cleavage of caspase-4 under the ER stress and results in the activation of caspase-9 and caspase-3, apoptosis signal, without releasing cytochrome-c. (C) 2007 Elsevier Ltd. All rights reserved.
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