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

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Abstract
Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloidβ protein (Aβ) 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 Aβ. 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 Aβ. 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 Aβ-induced neurotoxicity. Treatment of cultures with AC187 before exposure to Aβ results in significantly improved neuronal survival as judged by MTT and live-dead cell assays. Quantitative measures of Aβ-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 Aβ-induced apoptotic cell death. These data are the first to show that expression of Aβ toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD.