Skip to main content
U.S. flag

An official website of the United States government

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


Year of Publication:
Contact PI Name:
Frank M. LaFerla
Contact PI Affiliation:
Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, USA
Kim N. Green, Joan S. Steffan, Hilda Martinez-Coria, Xuemin Sun, Steven S. Schreiber, Leslie Michels Thompson
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer's Drug Discovery Foundation (ADDF)
Study Goal and Principal Findings:

The goal of this study was to evaluate the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs, in 3xTg mice. Data found that oral nicotinamide treatment restored cognitive deficits that manifest in the 3xTg-AD mice, while improving short-term spatial memory in non-demented control animals.  However, nicotinamide treatment had no significant effects on beta amyloid load or, beta amyloid peptide production. Tau pathology is decreased following nicotinamide treatment, and drug treatment was found to selectively reduce a phosphorylated species of tau ( phosphoThr231-tau) associated with microtubule depolymerization and implicated in AD. Nicotinamide  had no effect on the levels of cyclin-dependent kinase 5 (cdk5) and GSK3β but did up regulate p25 which is linked to improved learning and memory.  In addition, treatment inhibited brain sirtuins,  increased acetylated -tau,upregulated proteins associated with increased microtubule stabilization such as SirT2, and MAP2c and reduced ubiquninated 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Histone Deacetylases

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Fear Conditioning Response
Novel Object Recognition Test (NORT)
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP) Metabolites
Ubiquitinated Tau
Acetylated Tubulin
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Cyclin-Dependent Kinase 5 (CDK5)
p25/p35/Cyclin-Dependent Kinase 5 Regulatory Subunit 1 (CDK5R1)
Microtubule-Associated Protein 2 (MAP2)