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Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease


Year of Publication:
Contact PI Name:
Frank M. LaFerla
Contact PI Affiliation:
Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, USA
Salvatore Oddo, Antonella Caccamo, Kim N. Green, Kevin Liang, Levina Tran, Yiling Chen, Frances M. Leslie
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
National Institute on Drug Abuse (NIDA)
Study Goal and Principal Findings:

The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer’s disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on Aβ accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on Aβ and tau pathology, this study chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, they show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. They also show that the 3xTg-AD mice have an age-dependent reduction of 7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of 7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal Aβ42 accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either Aβ or tau. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Nicotinic Cholinergic Receptor

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
Neurofibrillary Tau Tangles
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
p38 Mitogen-Activated Protein Kinase (p38 MAPK)
Glycogen Synthase Kinase 3 alpha (GSK3 alpha)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
Cyclin-Dependent Kinase 5 (CDK5)
Amyloid Precursor Protein (APP)
APP-CTF99 (CTF beta)
Extracellular Signal-Regulated Kinase 1/2 (ERK1/2)
Total Tau Protein
Brain-beta Amyloid Deposits
Tau Protein
Nicotinic Cholinergic Receptor alpha 7 Subunit