Kroker_2013_Brain.Res.Bull_96C_28

As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between alpha4beta2, alpha7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (Abeta)42 oligomers, which are believed to be the synaptotoxic Abeta-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the alpha4beta2 nAChR agonist TC-1827 and the alpha7 nAChR partial agonist SSR180711 to reverse Abeta42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of Abeta42 oligomer induced impairment of early LTP, and had no effect on Abeta42 oligomer induced impairment of late LTP. The same was demonstrated for the alpha4beta2 nAChR agonist TC-1827. In contrast, the alpha7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by Abeta42 oligomers. As activating alpha7 nAChRs was found to be most efficacious in restoring Abeta42 oligomer induced LTP deficits, targeting alpha7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD.