Amyloid β-peptide disrupts carbachol-induced muscarinic holinergic signal transduction in cortical neurons

Jeremiah F. Kelly, Katsutoshi Furukawa, Steven W. Barger, Mohan R. Rengen, Robert J. Mark, Emmanuelle M. Blanc, George S. Roth, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)

Abstract

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid β-peptide (Aβ), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Aβ25-35 and Aβ1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Aβ. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Aβ. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to Aβ. The effects of Aβ on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Aβ induced uncoupling of muscarinic receptors. These data demonstrate that Aβ disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Aβ in the impairment of cholinergic transmission that occurs in AD.

Original languageEnglish
Pages (from-to)6753-6758
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number13
DOIs
Publication statusPublished - 1996 Jun 25

Keywords

  • Acetylcholine
  • Alzheimer disease
  • Antioxidant
  • Calcium
  • Carbachol

ASJC Scopus subject areas

  • General

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