Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau

J Neurosci. 2008 Nov 5;28(45):11500-10. doi: 10.1523/JNEUROSCI.3203-08.2008.

Abstract

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 alpha-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Behavior, Animal / drug effects
  • Butyrates / pharmacology
  • Cell Line, Transformed
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Immunoprecipitation / methods
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Mutation / genetics
  • Niacinamide / therapeutic use*
  • Peptide Fragments / metabolism
  • Phosphorylation / drug effects
  • Presenilin-1 / genetics
  • Sirtuins / metabolism*
  • Threonine / metabolism*
  • Time Factors
  • Transfection
  • Tubulin / metabolism
  • Vitamin B Complex
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Butyrates
  • Enzyme Inhibitors
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Peptide Fragments
  • Presenilin-1
  • Tubulin
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Vitamin B Complex
  • Niacinamide
  • Threonine
  • Sirtuins