title: Actions of β-amyloid protein on human neurons are expressed through the amylin receptor.
abstract: Disruption of neurotoxic effects of amyloid β protein (Aβ) is one of the major, but as yet elusive, goals in the treatment of Alzheimer's disease (AD). The amylin receptor, activated by a pancreatic polypeptide isolated from diabetic patients, is a putative target for the actions of Aβ in the brain. Here we show that in primary cultures of human fetal neurons (HFNs), AC253, an amylin receptor antagonist, blocks electrophysiological effects of Aβ. Pharmacological blockade of the amylin receptor or its down-regulation using siRNA in HFNs confers neuroprotection against oligomeric Aβ-induced caspase-dependent and caspase-independent apoptotic cell death. In transgenic mice (TgCRND8) that overexpress amyloid precursor protein, amylin receptor is up-regulated in specific brain regions that also demonstrate an elevated amyloid burden. The expression of Aβ actions through the amylin receptor in human neurons and temporospatial interrelationship of Aβ and the amylin receptor in an in vivo model of AD together provide a persuasive rationale for this receptor as a novel therapeutic target in the treatment of AD.
authors.affiliation: Division of Neurology, University of Alberta, Edmonton, Alberta, Canada. jack.jhamandas@ualberta.ca
authors.forename: Jack H
authors.initials: JH
authors.lastname: Jhamandas
authors.forename: Zongming
authors.initials: Z
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Simran
authors.initials: S
authors.lastname: Jassar
authors.forename: David
authors.initials: D
authors.lastname: MacTavish
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D019610:Cytoprotection; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D058287:Receptors, Islet Amyloid Polypeptide