title: Par-4 induces cholinergic hypoactivity by suppressing ChAT protein synthesis and inhibiting NGF-inducibility of ChAT activity.
abstract: 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.
authors.affiliation: Department of Neurobiology and Pharmacology, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, PO Box 95, Rootstown, OH 44272-0095, USA. qguo@neoucom.edu
authors.forename: Q
authors.initials: Q
authors.lastname: Guo
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: H
authors.initials: H
authors.lastname: Du
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D016350:Leucine Zippers / Q000235:genetics; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009994:Osmolar Concentration; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C101296:prostate apoptosis response-4 protein; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase