Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons.
Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloidbeta protein (Abeta) 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 Abeta. 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 Abeta. 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 Abeta-induced neurotoxicity. Treatment of cultures with AC187 before exposure to Abeta results in significantly improved neuronal survival as judged by MTT and live-dead cell assays. Quantitative measures of Abeta-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 Abeta-induced apoptotic cell death. These data are the first to show that expression of Abeta toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD.
Jhamandas
Jack H
JH
Division of Neurology, Department of Medicine, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. jack.jhamandas@ualberta.ca
MacTavish
David
D
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D015151:Immunoblotting; D007150:Immunohistochemistry; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; C087166:AC 187; D020169:Caspases