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J. Biol. Chem., Vol. 279, Issue 36, 37842-37851, September 3, 2004

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-Amyloid Directly Inhibits Human 42-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells^*

Jie Wu, Yen-Ping Kuo¶, Andrew A. George¶, Lin Xu¶, Jun Hu, and Ronald J. Lukas¶

From the Division of Neurology and the ^¶Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013-4496

Amyloid- (A) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimer's disease (AD). In AD, there is a selective decrease in the numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human 4 and 2 subunits (h42-nAChR). However, the relationships between these phenomena are uncertain, and effects of A on h42-nAChR function have not been investigated in detail. We first confirmed expression of h4 and h2 subunits as messenger RNA in transfected, human SHEP1 cells by reverse transcription-polymerase chain reaction and mRNA fluorescence in situ hybridization analyses. Immunoprecipitation Western analyses confirmed 4 and 2 subunit protein expression and co-assembly. Whole cell current recording demonstrated heterologous expression in SH-EP1-h42 cells of functional h42-nAChRs with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole cell currents were suppressed by A_1-42 in a dose-dependent manner. Functional inhibition was selective for A_1-42 compared with the functionally inactive, control peptide A_40-1.A_1-42-mediated inhibition of h42-nAChR function was non-competitive, voltage-independent, and use-independent. Pre-loading of cells with guanyl-5'-yl thiophosphate failed to prevent A_1-42-induced inhibition, suggesting that down-regulation of h42-nAChR function by A_1-42 is not mediated by nAChR internalization. Sensitivity to A_1-42 antagonism at 1 nM was evident for h42-nAChRs, but not for heterologously expressed human 7-nAChRs, although both nAChR subtypes were functionally inhibited by 100 nM A_1-42, with the magnitude of functional block being higher for 100 nM A_1-42 acting on h7-nAChRs. These findings suggest that h42-nAChRs are sensitive and perhaps pathophysiologically relevant targets for A neurotoxicity in AD.

Received for publication, January 13, 2004 , and in revised form, July 1, 2004.

^* This work was supported by an Arizona Alzheimer's Disease Center pilot grant and the Marjorie Newsome and Sandra Solheim Aiken fund (to J. W.). Other work toward this project, part of which was conducted in the Charlotte and Harold Simensky Neurochemistry of Alzheimer's Disease Laboratory, was supported by endowment and/or capitalization funds from the Men's and Women's Boards of the Barrow Neurological Foundation, the Robert and Gloria Wallace Foundation, Arizona Disease Control Research Commission Grants 9615 and 1-353, and National Institutes of Health Grant NS040417 (to R. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Rd., Phoenix, AZ 85013-4496. Tel.: 602-406-6376; Fax: 602-406-7172; E-mail: jwu2{at}chw.edu.

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