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The Journal of Neuroscience, June 16, 2004, 24(24):5579-5584; doi:10.1523/JNEUROSCI.1051-04.2004

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

Jack H. Jhamandas and David MacTavish

Division of Neurology, Department of Medicine, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

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.

Key words: AC187; Alzheimer's disease; diagonal band of Broca; neurodegeneration; apoptosis; caspase

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Received March 22, 2004; revised May 3, 2004; accepted May 4, 2004.

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				L. Saavedra, A. Mohamed, V. Ma, S. Kar, and E. P. de Chaves Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E J. Biol. Chem., December 7, 2007; 282(49): 35722 - 35732. [Abstract] [Full Text] [PDF]

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