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Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease
Open accessAbstract
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 Aβ 42 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.
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“Elevated p38 activity is found in brains from patients with tauopathies (145–147) and in transgenic AD mice models expressing human tau (148–150) or mutant APP (151), both of which correlate with tau aggregation.”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [150]
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Metadata
- Authors
- Oddo, S., Caccamo, A., Green, K. N., Liang, K., Tran, L., Chen, Y., Leslie, F. M., & LaFerla, F. M.
- Affiliations
- University of California, Irvine (US)
- Departments of Neurobiology and Behavior and Pharmacology, University of California, Irvine, CA 92697
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-02-10
- Volume
- 102
- Issue
- 8
- Pages
- 3046-3051
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC549455
- OpenAlex
- W2139557860
- Cited by
- 211
- References
- 47
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 14 · 2013: 14 · 2012: 11
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institute on Aging (AG0212982)
- National Institute on Drug Abuse (DA-10612, R01DA010612)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- chronic nicotine administration, tau pathology, Alzheimer's disease, nicotinic acetylcholine receptors, alpha7 nicotinic acetylcholine receptor, tau phosphorylation, p38 MAPK, amyloid-beta deposition, 3xTg-AD mice
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Calcium, Disease Models, Animal, Mice, Transgenic, Nicotine, Phosphorylation, Receptors, Nicotinic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Mice, alpha7 Nicotinic Acetylcholine Receptor
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