title: Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice.
abstract: Alzheimer's disease (AD) is associated with cognitive and non-cognitive symptoms for which there are currently no effective therapies. We have previously reported that cotinine, a natural product obtained from tobacco leaves, prevented memory loss and diminished amyloid-β (Aβ) plaque pathology in transgenic 6799 mice (Tg6799 mice) when treated prior to the development of the pathology. We have also shown that cotinine reduces depressive-like behavior in normal and chronically stressed C57BL/6 mice. Here, we extend our previous studies by investigating the effects of cotinine on the progression of AD-like pathology, depressive-like behavior, and the mechanisms underlying its beneficial effects in Tg6799 mice when left untreated until after a more advanced stage of the disease's development. The results show that vehicle-treated Tg6799 mice displayed an accentuated loss of working memory and an abundant Aβ plaque pathology that were accompanied by higher levels of depressive-like behavior as compared to control littermates. By contrast, prolonged daily cotinine treatment to Tg6799 mice, withheld until after a mid-level progression of AD-like pathology, reduced Aβ levels/plaques and depressive-like behavior. Moreover, this treatment paradigm dramatically improved working memory as compared to control littermates. The beneficial effects of cotinine were accompanied by an increase in the expression of the active form of protein kinase B and the postsynaptic density protein 95 in the hippocampi and frontal cortices of Tg6799 mice. This suggests that cotinine halts the progression of AD-like pathology while reducing depressive-like behavior by stimulating signaling pathways supporting synaptic plasticity in Tg6799 mice. The potential use of cotinine to treat cognitive and non-cognitive symptoms of AD is discussed.
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Patel
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA ; Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: J Alex
authors.initials: JA
authors.lastname: Grizzell
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Rosalee
authors.initials: R
authors.lastname: Holmes
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Zeitlin
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Rosalynn
authors.initials: R
authors.lastname: Solomon
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Sutton
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Rohani
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Charry
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA ; Center of Research in Biomedical Sciences, Universidad Autónoma de Chile Santiago, Chile.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Iarkov
authors.affiliation: Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University Kawagoe, Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.affiliation: Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System Bay Pines, FL, USA ; Center of Research in Biomedical Sciences, Universidad Autónoma de Chile Santiago, Chile ; Research Service, Department of Veterans Affairs, Tampa VA Healthcare System Tampa, FL, USA ; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida Tampa, FL, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Echeverria Moran
keywords: Akt; Alzheimer's disease; amyloid-β; cotinine; depression; memory loss; postsynaptic density protein 95; protein kinase B
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