期刊
BRAIN RESEARCH
卷 874, 期 2, 页码 221-232出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0006-8993(00)02559-2
关键词
Alzheimer's disease; Par-4; choline acetyl-transferase; nerve growth factor; amyloid beta peptide; neurotransmitter
Profound reductions in choline acetyl-transferase (ChAT) activity are reliable markers for cholinergic hypoactivity associated with cognitive function deficit in Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a novel mediator of neuronal apoptosis associated with the pathogenesis of AD. Par-4 contains a leucine zipper domain (Leu.zip) that presumably mediates protein-protein interactions critical for its functions in apoptosis. Par-4 activity can be effectively blocked by overexpression of Leu.zip because it exerts a dominant negative action possibly by competitively blocking the interaction of Par-4 wit other proteins. Whether Par-4 participates in regulation of cholinergic signaling has not been determined. We report that overexpression of Par-4 results in apoptotic and non-apoptotic reductions in ChAT activity in transfected PC12 cells following exposure to a toxic concentration (50 mu M) of aggregated amyloid beta peptide 1-42 (A beta 1-42) and a nan-toxic concentration (1 mu M) of soluble A beta 1-42, respectively. Non-apoptotic reduction in ChAT activity induced by Par-4 can be completely blocked by co-overexpression of Leu.zip, indicating that enhanced Par-4 activity is a necessary event for cholinergic hypoactivity in PC12 cells. Further studies found that Par-4 induces non-apoptotic reduction in ChAT activity by: (1) reducing ChAT protein levels following exposure to non-toxic concentration of A beta, and (2) blocking the cellular capability to increase ChAT activity following exposure to nerve growth factor (NGF). The role of Par-4 in inducing cholinergic hypoactivity may have significant implications in the understanding and the treatment of memory impairment in AD. (C) 2000 Elsevier Science B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据