AMYLOID BETA-PEPTIDE DISRUPTS CARBACHOL-INDUCED MUSCARINIC CHOLINERGIC SIGNAL-TRANSDUCTION IN CORTICAL-NEURONS

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberat ion of inositol trisphosphate and Ca2+ release from intracellular stor es, We now report that amyloid beta-peptide (A beta), which forms plaq ues in the brain in AD, impairs muscarinic receptor activation of C pr oteins in cultured rat cortical neurons, Exposure of rodent fetal cort ical neurons to A beta 25-35 and A beta L-40 resulted in a concentrati on and time-dependent attenuation of Carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters, Down stream events in the signal transduction cascade were similarly attenu ated by A beta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies reve aled that carbachol-induced release of calcium was severely impaired i n neurons pretreated with A beta. Muscarinic cholinergic signal transd uction was disrupted with subtoxic levels of exposure to A beta. The e ffects of A beta on carbachol-induced GTPase activity and calcium rele ase were attenuated by antioxidants, implicating free radicals in the mechanism whereby A beta induced uncoupling of muscarinic receptors, T hese data demonstrate that A beta disrupts muscarinic receptor couplin g to G proteins that mediate induction of phosphoinositide accumulatio n and calcium release, findings that implicate A beta in the impairmen t of cholinergic transmission that occurs in AD.