TY - JOUR
T1 - Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice
AU - Echeverria, Valentina
AU - Zeitlin, Ross
AU - Burgess, Sarah
AU - Patel, Sagar
AU - Barman, Arghya
AU - Thakur, Garima
AU - Mamcarz, Magorzota
AU - Wang, Li
AU - Sattelle, David B.
AU - Kirschner, Daniel A.
AU - Mori, Takashi
AU - Leblanc, Roger M.
AU - Prabhakar, Rajeev
AU - Gary, Gary W.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - amyloid-β
KW - cotinine
KW - neurodegeneration
KW - oligomerization
UR - http://www.scopus.com/inward/record.url?scp=79959218579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959218579&partnerID=8YFLogxK
U2 - 10.3233/JAD-2011-102136
DO - 10.3233/JAD-2011-102136
M3 - Article
C2 - 21321389
AN - SCOPUS:79959218579
VL - 24
SP - 817
EP - 835
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 4
ER -