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J. Biol. Chem., Vol. 283, Issue 20, 14132-14143, May 16, 2008

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p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis^*

Qiu-Lan Ma, Fusheng Yang, Frédéric Calon^¶||, Oliver J. Ubeda, James E. Hansen, Richard H. Weisbart, Walter Beech, Sally A. Frautschy^**, and Greg M. Cole^**1

From the Departments of Medicine and ^**Neurology, UCLA, Los Angeles, California, Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Veterans Affairs Medical Center, North Hills, California 91343, and ^¶Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, Québec City, Québec G1V 4G2, Canada, and ^||Faculty of Pharmacy, Laval University, Québec City, Québec G1K 7P4, Canada

Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actin-regulatory protein Drebrin. β-Amyloid (Aβ) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. Aβ₄₂ oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. Aβ₄₂ oligomer treatment also significantly reduced N-methyl-D-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in Aβ₄₂ oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be Aβ-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in Aβ₄₂ oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in Aβ oligomer-induced signaling and synaptic deficits in Alzheimer disease.

Received for publication, September 26, 2007 , and in revised form, March 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG16570 (to G. M. C.), AG13471 (to G. M. C.), U0128583 (to S. A. F.), and AG021975 (to S. A. F.). This work was also supported by National Center on Complementary and Alternative Medicine Grant AT003008 (to G. M. C.) and Alzheimer Association Grant NIRG-07-59659 (to Q.-L. M.). 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.

¹ To whom correspondence should be addressed: Greater Los Angeles Veterans Affairs Healthcare System Alzheimer Research-151, Bldg. 7, Rm. A102, 16111 Plummer St., North Hills, CA 91343. Fax: 818-895-5835; E-mail: gmcole{at}ucla.edu.