Par-4 induces cholinergic hypoactivity by suppressing ChAT protein synthesis and inhibiting NGF-inducibility of ChAT activity

被引:14
作者
Guo, Q
Xie, J
Du, HM
机构
[1] Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Neurobiol & Pharmacol, Rootstown, OH 44272 USA
[2] Case Western Reserve Univ, Dept Human Genet, Cleveland, OH 44106 USA
关键词
Alzheimer's disease; Par-4; choline acetyl-transferase; nerve growth factor; amyloid beta peptide; neurotransmitter;
D O I
10.1016/S0006-8993(00)02559-2
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:221 / 232
页数:12
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