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PMID: 8692890 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 93 ·No. 13 ·1996-06-25 ·Pages 6753-8

Kelly JF, Furukawa K, Barger SW, Rengen MR, Mark RJ, Blanc EM, Roth GS, Mattson MP

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 beta-peptide (Abeta), 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 Abeta25-35 and Abeta1-40 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 Abeta. 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 Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD.

MeSH Terms
Amyloid beta-Peptides/metabolism Animals Antioxidants/pharmacology Calcium/metabolism Carbachol/pharmacology Cells, Cultured Cerebral Cortex/cytology,drug effects,enzymology,metabolism Enzyme Induction GTP Phosphohydrolases/biosynthesis,metabolism Inositol Phosphates/metabolism Neurons/drug effects,enzymology,metabolism Peptide Fragments/metabolism Rats Rats, Sprague-Dawley Reactive Oxygen Species Receptors, Muscarinic/metabolism Signal Transduction
Chemicals
Amyloid beta-Peptides Antioxidants Inositol Phosphates Peptide Fragments Reactive Oxygen Species Receptors, Muscarinic amyloid beta-protein (1-43) Carbachol GTP Phosphohydrolases Calcium
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Kelly J F
Molecular Physiology and Genetics Section, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA.
Furukawa K
Barger S W
Rengen M R
Mark R J
Blanc E M
Roth G S
Mattson M P
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.93.13.6753
Published
1996-06-25
Pages
6753-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC39099
Subset
IM
Grants
NIA NIH HHS · AG10836 · United States
NINDS NIH HHS · NS30538 · United States
External Links
PubMed source DOI: 10.1073/pnas.93.13.6753 PMC Full Text View journal details
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