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Originally published In Press as doi:10.1074/jbc.M209892200 on February 26, 2003

J. Biol. Chem., Vol. 278, Issue 19, 17546-17556, May 9, 2003
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Activation of Muscarinic Receptors Inhibits beta -Amyloid Peptide-induced Signaling in Cortical Slices*

Zhenglin Gu, Ping Zhong, and Zhen YanDagger

From the Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214

Deposition of fibrillar aggregates of the beta -amyloid peptide (Abeta ) is a key pathologic feature during the early stage of Alzheimer's disease. The initial neuronal responses to Abeta in cortical circuits and the regulation of Abeta -induced signaling remain unclear. In this study, we found that exposure of cortical slices to Abeta 1-42 or Abeta 25-35 induced a marked increase in the activation of protein kinase C (PKC) and Ca2+/calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the Abeta activation of PKC and CaMKII. Increasing inhibitory transmission mimicked the M1 effect on Abeta , whereas blocking GABAA receptors eliminated the M1 action. Moreover, electrophysiological evidence shows that application of Abeta to cortical slices induced action potential firing and enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently increased inhibitory postsynaptic currents. These results suggest that Abeta activates PKC and CaMKII through enhancing excitatory activity in glutamatergic synaptic networks. Activation of M1 receptors inhibits Abeta signaling by enhancing the counteracting GABAergic inhibitory transmission. Thus the muscarinic reversal of the Abeta -induced biochemical and physiological changes provides a potential mechanism for the treatment of Alzheimer's disease with cholinergic enhancers.

* This work was supported by National Science Foundation Grant IBN-0117026 (to Z. Y.), National Institutes of Health Grant MH63128 (to Z. Y.), and Howard Hughes Medical Institute Biomedical Research Support Program Grant 53000261 (to SUNY at Buffalo).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214. E-mail: zhenyan@buffalo.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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