Cotinine: a potential new therapeutic agent against Alzheimer's disease

Abstract

Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.

Figure 1

Comparison of the structures of cotinine and nicotine.

Figure 2

Hypothetical model of cotinine's potentiation of the α7 nAChR. The scheme represents the hypothetical positive allosteric modulation of the α7 nAChR by cotinine, and the activation of signaling pathways that are downstream of the a7 nAChR. The consequences of the activation by cotinine of components of the PI3K‐Akt‐GSK3β pathway on AD pathology are suggested. The activation of Akt by cotinine may result in the inhibition of the tau kinase GSK3β and consequently the formation of hyperphosphorylated forms of tau found in the neurofibrillary tangles (one of the neuropathological hallmarks of AD). Also, the inhibition of GSK3β may inhibit its pro‐apoptotic effect. On the other hand, the stimulation of pERK can stimulate pCREB activity and as a result stimulate the expression of Arc, a protein that participate in the remodeling of the synapses during learning and memory processes and is required for long‐term memory. CREB stimulate the expression of antiapoptotic factors such as Bcl2.