The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081588
The Journal of Experimental Medicine, Vol. 205, No. 12, 2781-2789
The Rockefeller University Press, 0022-1007 $30.00
© Qing et al.
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ARTICLE

 Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

Hong Qing1, Guiqiong He1,3, Philip T. T. Ly1,2, Christopher J. Fox1,2, Matthias Staufenbiel4, Fang Cai1, Zhuohua Zhang5, Shengcai Wei1, Xiulian Sun1,2, Chia-Hsiung Chen1,2, Weihui Zhou1, Ke Wang1,2, and Weihong Song1,2

1 Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, 2 Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
3 Department of Human Anatomy, Chongqing University of Medical Sciences, Chongqing 400016, China
4 Novartis Institutes for Biomedical Research Basel, CH-4002 Basel, Switzerland
5 Center for Neuroscience and Aging, The Burnham Institute, La Jolla, CA 92037

CORRESPONDENCE Weihong Song: weihong{at}interchange.ubc.ca

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and {gamma}-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated {gamma}-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

Abbreviations used: Aβ, amyloid β-protein; AD, Alzheimer's disease; APP, β-amyloid precursor protein; BACE, β-site APP cleaving enzyme; CTF, C-terminal fragment; GSK, glycogen synthase kinase; HDAC, histone deacetylase; MAP, microtubule-associated protein; VPA, valproic acid.

H. Qing, G. He, and P.T.T. Ly contributed equally to this paper.

© 2008 Qing et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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