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J. Biol. Chem., Vol. 280, Issue 48, 40364-40374, December 2, 2005

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SIRT1 Protects against Microglia-dependent Amyloid- Toxicity through Inhibiting NF-B Signaling^*

Jennifer Chen1, Yungui Zhou1, Sarah Mueller-Steiner, Lin-Feng Chen¶, Hakju Kwon¶, Saili Yi, Lennart Mucke, and Li Gan2

From the Gladstone Institute of Neurological Disease, ^¶Gladstone Institute of Virology and Immunology, and Department of Neurology, University of California, San Francisco, California 94158

Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-B signaling in microglia is critically involved in neuronal death induced by amyloid- (A) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-B signaling in microglia by expression of the nondegradable IB superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-B signaling in mediating A toxicity. Stimulation of microglia with A increased acetylation of RelA/p65 at lysine 310, which regulates the NF-B pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-B signaling stimulated by A and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-B signaling in A-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.

Received for publication, August 24, 2005 , and in revised form, September 22, 2005.

^* This work was supported in part by a pilot project grant from the University of California, San Francisco, Alzheimer's Disease Research Center, by a scholarship from the McBean Family Foundation (to L. G.), by National Institutes of Health Grant NS43945 (to L. M.), and by a fellowship from the Swiss Science Foundation (to S. M.-S.). 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

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed: Gladstone Institute of Neurological Disease, 1650 Owens St., University of California, San Francisco, CA 94158. Tel.: 415-734-2524; Fax: 415-355-0824; E-mail: lgan{at}gladstone.ucsf.edu.

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