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To determine the effects of chronic nicotine administration on A\u03b2 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<jats:italic>in vivo<\/jats:italic>. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>. We also show that the 3xTg-AD mice have an age-dependent reduction of \u03b17nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of \u03b17nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal A\u03b2<jats:sub>42<\/jats:sub>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 A\u03b2 or tau.<\/jats:p>","DOI":"10.1073\/pnas.0408500102","type":"journal-article","created":{"date-parts":[[2005,2,11]],"date-time":"2005-02-11T01:24:39Z","timestamp":1108085079000},"page":"3046-3051","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":163,"title":["Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease"],"prefix":"10.1073","volume":"102","author":[{"given":"Salvatore","family":"Oddo","sequence":"first","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Caccamo","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim N.","family":"Green","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Liang","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Levina","family":"Tran","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiling","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances M.","family":"Leslie","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank M.","family":"LaFerla","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"341","published-online":{"date-parts":[[2005,2,10]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"1403","volume":"2","year":"1976","unstructured":"Davies, P. & Maloney, A. 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