Cholinergic Muscarinic Receptor Signaling by the Phosphoinositide Signal Transduction System in Alzheimer's Disease *

Abstract

Recent years have seen the advent of new methods capable of measuring the activity of receptor-coupled, G-protein-mediated, phosphoino-sitide second messenger production in membranes prepared from postmortem human brain. Considering the interest in treating Alzheimer's disease (AD) patients with cholinergic agonists, several investiga-tions have used this new methodology to analyze the functional state of cholinergic muscarinic receptors coupled to phosphoinositide signaling directly in AD brain. Several, but not all, reports indicate that cholinergic agonist-induced phosphoinositide signaling is severely impaired in AD, potentially due to impaired activation of the receptor-coupled G-protein. Ad-ditionally, deficits in AD also have been reported in the two second messenger pathways activated following phosphoinositide hydrolysis, inositol-1,4,5,-triphos-phate receptor binding and protein kinase C activation, indicating further that phosphoinositide signaling is impaired in AD. Sources of limitations in current methodologies and issues for further exploration are discussed. Speculation concerning potential links between cholinergic receptor-linked signaling and early events in the formation of amyloid plaques and neurofibrillary tangles is provided. Especially intri-guing is the potential for the development of synergistic neurotoxicity where deficits of phosphoinositide signaling and increased production of Aβ interact to exacerbate alterations in each process that occur in AD, leading to a feed-forward cycle of progressive neuronal dysfunction.