Deletion of the α7 Nicotinic Acetylcholine Receptor Gene Improves Cognitive Deficits and Synaptic Pathology in a Mouse Model of Alzheimer's Disease

It has been recently shown that the Alzheimer's disease (AD) pathogenic peptide amyloid beta(1-42) (A beta(1-42)) binds to the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) with high affinity and the alpha 7nAChR and A beta(1-42) are both found colocalized in neuritic plaques of humanbrains with AD. Moreover, the intraneuronal accumulation of A beta(1-42) was shown to be facilitated by its high-affinity binding to the alpha 7nAChR, and alpha 7nAChR activation mediates A beta-induced tau protein phosphorylation. To test the hypothesis that alpha 7nAChRs are involved in AD pathogenesis, we used a transgenic mouse model of AD overexpressing a mutated form of the human amyloid precursor protein (APP) and lacking the alpha 7nAChRgene (APP alpha 7KO). We have shown that, despite the presence of high amounts of APP and amyloid deposits, deleting the alpha 7nAChR subunit in the mouse model of AD leads to a protection from the dysfunction in synaptic integrity (pathology and plasticity) and learning and memory behavior. Specifically, APP alpha 7KO mice express APP and A beta at levels similar to APP mice, and yet they were able to solve a cognitive challenge such as the Morris water maze test significantly better than APP, with performances comparable to control groups. Moreover, deleting the alpha 7nAChR subunit protected the brain from loss of the synaptic markers synaptophysin and MAP2, reduced the gliosis, and preserved the capacity to elicit long-term potentiation otherwise deficient in APP mice. These results are consistent with the hypothesis that the alpha 7nAChR plays a role in AD and suggest that interrupting alpha 7nAChR function could be beneficial in the treatment of AD.