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.

Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome

“…Several previous studies reported enhanced learning and memory after chronic cotinine administration in rodents (Terry et al ., , ; Buccafusco & Terry, ; Echeverria et al ., ; Moran, ; Gao et al ., ; Grizzell & Echeverria, ; Grizzell et al ., ; Patel et al ., ; Levin et al ., ). Chronic subcutaneous cotinine treatment did not significantly affect memory in wild‐type rats (Terry et al ., ), but chronic oral cotinine treatment enhanced spatial working memory in wild‐type mice compared to vehicle‐treated mice (Grizzell et al ., ).…”

“…Activation of nAChRs promotes the expression of synaptic proteins in the brain and enhances cognition in animal models (Buccafusco & Terry, ; Terry et al ., , ; McKay et al ., ; Grizzell et al ., ). For example, cotinine treatment restored impaired memory in mouse and monkey models of impaired hippocampal function (Echeverria et al ., ; Terry et al ., ; Gao et al ., ; Grizzell et al ., ; Patel et al ., ), ameliorated impaired cognition in mouse models of Alzheimer's disease, including working memory (Echeverria et al ., ; Patel et al ., ), memory deficits in animal models of schizophrenia (Buccafusco & Terry, ; Buccafusco et al ., ; Terry et al ., ) and stress‐related memory impairments (Zeitlin et al ., ; Grizzell et al ., ).…”

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

“…For example, relevant to AD, cotinine has been shown to be cytoprotective and neuroprotective as demonstrated by its ability to improve the survival of differentiated PC12 cells deprived of nerve growth factor [40], as well as to protect primary cortical neurons from the neurotoxic effects of the amyloid beta (Aβ) peptide or glutamate [41,42]. Cotinine also improved working/short term memory in a delayed match to sample (DMTS) task in monkeys [43], prevented memory loss in an AD mouse model (Tg6799), stimulated the Akt/GSK3β pathway and reduced Aβ aggregation in their brains [44,45]. In studies more relevant to schizophrenia, cotinine attenuated the deficits in prepulse inhibition (PPI) of the acoustic startle response induced in three pharmacologic impairment models in rats [43], it improved sustained attention in rats that were impaired by the NMDA receptor antagonist MK-801 [46], and it attenuated deficits in working/short term memory in monkeys produced by the NMDA antagonist ketamine [47].…”

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

“…For example, in studies relevant to AD, cotinine has been shown to improve the survival of differentiated PC12 cells deprived of nerve growth factor (Buccafusco and Terry, 2003), as well as primary cortical neurons exposed to toxic concentrations of the amyloid-b peptide or glutamate Gao et al, 2014). Cotinine has also been shown to improve working/short-term memory performance in monkeys (Terry et al, 2005), prevent memory loss in transgenic 6799 Alzheimer's disease mice, and stimulate the Akt/GSK3b pathway and reduce amyloid-b aggregation in mouse brains Patel et al, 2014). In animal studies more closely related to schizophrenia, cotinine improved deficits in prepulse inhibition of the acoustic startle response in rats in three pharmacologic impairment models (Terry et al, 2005), attenuated the deficits of sustained attention in rats induced by the N-methyl-D-aspartate receptor antagonist MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine] (Terry et al, 2012), and improved deficits in working/short-term memory produced by the N-methyl-D-aspartate antagonist ketamine in monkeys (Buccafusco and Terry, 2009).…”