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The Journal of Neuroscience, November 5, 2008, 28(45):11500-11510; doi:10.1523/JNEUROSCI.3203-08.2008

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Neurobiology of Disease
Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau

Kim N. Green,¹ Joan S. Steffan,² Hilda Martinez-Coria,¹ Xuemin Sun,³ Steven S. Schreiber,^3,5 Leslie Michels Thompson,^1,2,4 and Frank M. LaFerla¹

Departments of ¹Neurobiology and Behavior, ²Psychiatry and Human Behavior, ³Neurology, ⁴Biological Chemistry, and ⁵Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697-4545

Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu

Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD⁺-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated -tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.

Key words: amyloid; transgenic; Alzheimer's disease; vitamin; memory; cognition

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Received July 9, 2008; revised Aug. 27, 2008; accepted Sept. 7, 2008.

Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu

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