Oz_2013_Curr.Alzheimer.Res_10_618

Deterioration of the cortical cholinergic system is a leading neurochemical feature of Alzheimer's Disease (AD). This review summarizes evidence that the homomeric alpha7- nicotinic acetylcholine receptor (nAChR) plays a crucial role in the pathogenesis of this disease, which is characterized by amyloid-beta (Abeta) accumulations and neurofibrillary tangles originating from of hyperphosphorylated tau protein. Abeta binds to alpha7-nAChRs with a high affinity, either activating or inhibiting this receptor in a concentration-dependent manner. There is strong evidence that alpha7-nAChRs are neuroprotective, reducing Abeta-induced toxicity; but co-localization of alpha7- nAChRs, Abeta and amyloid plaques also points to neurodegenerative actions. Abeta induces tau phosphorylation via alpha7-nAChR activation. Abeta influences hippocampus-dependent memory and long-term potentiation in a dose-dependent way: there is evidence that enhancement by picomolar Abeta concentrations is mediated by alpha7-nAChRs, whereas inhibition by nanomolar concentrations is independent of nAChRs and probably mediated by small Abeta42 oligomers. alpha7-nAChRs located on vascular smooth muscle cells and astrocytes are also involved in the pathogenesis of AD. Although these data strongly point to an important role of alpha7-nAChRs in the development of AD, dose-dependence of the effects, rapid desensitization of the receptor and dependence of the effects on Abeta aggregation (monomers, oligomers, fibrils) make it difficult to develop simple therapeutic strategies acting upon this receptor.