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PMID: 10786716 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Amyloid beta peptide impaired carbachol but not glutamate-mediated phosphoinositide pathways in cultured rat cortical neurons.

Neurochemical research ·Vol. 25 ·No. 2 ·2000-02-00 ·Pages 303-12

Huang HM, Ou HC, Hsieh SJ

Abstract

Signal transduction systems, including cholinergic pathways, which are likely to be of pathophysiological significance are altered in Alzheimer's disease (AD). Muscarinic cholinergic receptors are linked to the hydrolysis of phosphoinositide, involving the production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and the mobilization of cytosolic free calcium concentrations ([Ca2+]i). Effects of amyloid peptide (A(beta)) on these signals prior to neuronal degeneration were examined in cultured rat cortical cells. A(beta) increased the release of lactate dehydrogenase (LDH) in a concentration-dependent manner, however, it was blocked by B27 supplement. Prolonged exposure to a sublethal dose of A(beta) 25-35 or 1-42 disrupted carbachol-mediated release of Ins(1,4,5)P3 and [Ca2+]i, which was inhibited in media supplemented with B27 or the antioxidant vitamin E. In order to determine the specificity of the effect of A(beta), various agonists glutamate or KCl but not bradykinin which utilize the phosphoinositide cascade were investigated. Our results indicated that A(beta) did not affect the stimulation of glutamate or KCl-mediated production of Ins(1,4,5)P3 or cause elevation in [Ca2+]i. Furthermore, metabotropic agonist trans-1-amino-cyclopentane-1,3,-dicarboxylate (ACPD) elevated calcium level was not inhibited by A(beta) pre-treatment. Taken together, the results demonstrate that a sublethal dose of A(beta) selectively impaired cholinergic receptor-mediated signal transduction pathways, and antioxidant or B27 supplement attenuated this effect of A(beta). Alterations of cholinergic signaling by prolonged exposure to A(beta) could be involved in cortical neurodegeneration that occurs in AD. Because functional loss of cholinergic pathways is an important aspect of AD, the differences in susceptibility of these two types of receptors prior to other signs of A(beta) action is important and requires further investigation.

MeSH Terms
Amyloid beta-Peptides/chemistry,physiology Animals Calcium/metabolism Carbachol/pharmacology Cells, Cultured Cerebral Cortex/cytology,drug effects,metabolism Glutamic Acid/pharmacology Inositol 1,4,5-Trisphosphate/biosynthesis Neurons/drug effects,metabolism Peptide Fragments/physiology Phosphatidylinositols/metabolism Rats
Chemicals
Amyloid beta-Peptides Peptide Fragments Phosphatidylinositols Glutamic Acid Inositol 1,4,5-Trisphosphate Carbachol Calcium
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Huang H M
Department of Education and Medical Research, Taichung Veterans General Hospital, Taiwan, ROC. [email protected]
Ou H C
Hsieh S J
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Article Info
Journal
Neurochemical research
Abbr.
Neurochem Res
ISSN
0364-3190
DOI
10.1023/a:1007592007956
Email
[email protected]
Published
2000-02-00
Pages
303-12
Language
English
Region
United States
NLM ID
7613461
Subset
IM
External Links
PubMed source DOI: 10.1023/a:1007592007956 View journal details
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