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J. Biol. Chem. 278 (34): 31547-31553

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

{alpha}7 Nicotinic Acetylcholine Receptors Mediate {beta}-Amyloid Peptide-induced Tau Protein Phosphorylation*

Hoau-Yan Wang {ddagger}, Weiwei Li, Nancy J. Benedetti, and Daniel H. S. Lee §

Biogen Inc., Cambridge, Massachusetts 02142 and {ddagger}Department of Physiology & Pharmacology, City University of New York Medical School, New York, New York 10031

Abstract: The Alzheimer's disease pathogenic peptide, {beta}-amyloid42 (A{beta}42), induces tau protein phosphorylation. Because hyperphosphorylated tau is a consistent component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease, we investigated the signaling molecules involved in A{beta}42-induced tau phosphorylation. We show that A{beta}42 elicited rapid and reversible tau protein phosphorylation on three proline-directed sites (Ser-202, Thr-181, and Thr-231) in systems enriched in {alpha}7 nicotinic acetylcholine receptors ({alpha}7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although {alpha}7nAChR agonists induced similar phosphorylation, pretreatment with antisense-{alpha}7nAChR oligonucleotides (in cells) or {alpha}7nAChR antagonists (in cells and synaptosomes) attenuated A{beta}-induced tau phosphorylation. Western analyses showed that the mitogen-activated kinase cascade proteins, ERKs and c-Jun N-terminal kinase (JNK-1), were concomitantly activated by A{beta}42, and their respective kinase inhibitors suppressed A{beta}-induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the {alpha}7nAChR may mediate A{beta}-induced tau protein phosphorylation via ERKs and JNK-1.

Received for publication December 9, 2002. Revision received June 2, 2003.

* 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: Biogen Inc., 14 Cambridge Center, Cambridge, MA 02142. Tel.: 617-679-2563; Fax: 617-679-3200; E-mail: Daniel_Lee{at}

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