Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice

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 Aβ1-42 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-Aβ1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Aβ1-42, 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.

Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease

“…Furthermore, it was reported that nicotine can decrease amyloid precursor protein (APP) secretion in animal models 10,11 , inhibit acquisition of b-sheet conformation by Ab peptide 12 , diminish its aggregation 13 , reduce bamyloidosis 14 and prevent memory impairment 15 . In fact, cotinine, the main metabolite of nicotine, is able to reduce Ab deposition by inhibiting its oligomerization and decrease memory impairment in transgenic AD mice 16 . Moreover, some studies have found that smoking is able to reduce Ab42 levels both in control and AD patients 17 .…”

Cotinine Inhibits Amyloid-β Peptide Neurotoxicity and Oligomerization

“…It has been shown that cotinine binds to Aβ with high affinity (K a =10 nM) [10] inhibiting its aggregation into fibrils in vitro [11]. A previous study also showed that cotinine reduced oligomeric Aβ levels in vivo [2]. However, whether the reduction in Aβ 1−42 oligomers was induced by a decrease in the peptide oligomerization it was not defined.…”

“…Previous evidence obtained in vivo [2] and this in vitro evidence suggests that cotinine has the potential to be a new pharmacological therapy against AD. .…”

“…Cotinine treatment reduced Aβ 1-42 oligomers levels in the brain of AD mice [2]. To determine whether this decrease was due to a decrease in the oligomerization of the peptide, dot-blot immunoassay analysis was performed on Aβ oligomerization solutions incubated for 2 and 6 days at RT.…”

“…Recently, it has been shown that cotinine prevented cognitive impairment and Aβ burden in a mouse model of AD [2].…”