Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice

Valentina Echeverria, Ross Zeitlin, Sarah Burgess, Sagar Patel, Arghya Barman, Garima Thakur, Magorzota Mamcarz, Li Wang, David B. Sattelle, Daniel A. Kirschner, Takashi Mori, Roger M. Leblanc, Rajeev Prabhakar, Gary W. Gary

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-β (Aβ) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Aβ deposition, improved working and reference memories, and inhibited Aβ oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Aβ 1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition of glycogen synthase kinase 3β (GSK3β), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and Tg6799 AD mice. Simulation of the cotinine-Aβ 1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Aβ 1-42, altering its structure and inhibiting its aggregation. The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of AD.

Original languageEnglish (US)
Pages (from-to)817-835
Number of pages19
JournalJournal of Alzheimer's Disease
Volume24
Issue number4
DOIs
StatePublished - 2011

Keywords

  • Alzheimer's disease
  • amyloid-β
  • cotinine
  • neurodegeneration
  • oligomerization

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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    Echeverria, V., Zeitlin, R., Burgess, S., Patel, S., Barman, A., Thakur, G., Mamcarz, M., Wang, L., Sattelle, D. B., Kirschner, D. A., Mori, T., Leblanc, R. M., Prabhakar, R., & Gary, G. W. (2011). Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice. Journal of Alzheimer's Disease, 24(4), 817-835. https://doi.org/10.3233/JAD-2011-102136