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

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

Guo Q; Xie J; Du H

Brain research

2000

2000-08

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 with 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 microM) of aggregated amyloid beta peptide 1-42 (Abeta 1-42) and a non-toxic concentration (1 microM) of soluble Abeta 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 Abeta, 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.

*Intracellular Signaling Peptides and Proteins; Amyloid beta-Peptides/pharmacology; Animals; Apoptosis Regulatory Proteins; Carrier Proteins/genetics/*physiology; Choline O-Acetyltransferase/*antagonists & inhibitors/biosynthesis/metabolism; Enzyme Induction/drug effects; Gene Expression/physiology; Leucine Zippers/genetics; Nerve Growth Factor/*pharmacology; Osmolar Concentration; PC12 Cells; Peptide Fragments/pharmacology; Rats

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