Brief Communication Antagonist of the Amylin Receptor Blocks -Amyloid Toxicity in Rat Cholinergic Basal Forebrain Neurons

Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloid protein (A ) is one of the major, but still elusive, therapeutic goals of current research in Alzheimer’s disease (AD). To date, no receptor has been unequivocally identified for A . Human amylin, which acts via a receptor composed of the calcitonin receptor-like receptor and a receptor-associated membrane protein, possesses amyloidogenic properties and has a profile of neurotoxicity that is strikingly similar to A . In this study, using primary cultures of rat cholinergic basal forebrain neurons, we show that acetyl-[Asn30, Tyr32] sCT(8 –37) (AC187), an amylin receptor antagonist, blocks A -induced neurotoxicity. Treatment of cultures with AC187 before exposure to A results in significantly improved neuronal survival as judged by MTT and live– dead cell assays. Quantitative measures of A -evoked apoptotic cell death, using Hoechst and phosphotidylserine staining, confirm neuroprotective effects of AC187. We also demonstrate that AC187 attenuates the activation of initiator and effector caspases that mediate A -induced apoptotic cell death. These data are the first to show that expression of A toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD.