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

Author:

Qing Hong1,He Guiqiong12,Ly Philip T. T.13,Fox Christopher J.13,Staufenbiel Matthias4,Cai Fang1,Zhang Zhuohua5,Wei Shengcai1,Sun Xiulian13,Chen Chia-Hsiung13,Zhou Weihui1,Wang Ke13,Song Weihong13

Affiliation:

1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center

2. Department of Human Anatomy, Chongqing University of Medical Sciences, Chongqing 400016, China

3. Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC V6T 1Z3, Canada

4. Novartis Institutes for Biomedical Research Basel, CH-4002 Basel, Switzerland

5. Center for Neuroscience and Aging, The Burnham Institute, La Jolla, CA 92037

Abstract

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 γ-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 γ-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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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