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

Salvatore Oddo, Antonella Caccamo, Kim N. Green, Kevin Liang, Levina Tran, Yiling Chen, Frances M. Leslie, Frank M. LaFerla

Research output: Contribution to journalArticlepeer-review

171 Scopus citations


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, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we 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. We also show that the 3xTg-AD mice have an age-dependent reduction of α7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of α7nAChRs 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.

Original languageEnglish (US)
Pages (from-to)3046-3051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
StatePublished - Feb 22 2005
Externally publishedYes


  • Plaques
  • Tangles
  • β-amyloid-3xTg-AD

ASJC Scopus subject areas

  • General


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