Ni_2013_J.Alzheimers.Dis_33_841

The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-beta (Abeta) assemblies bind to alpha7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Abeta by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Abeta. The alpha7 nAChR agonists varenicline and JN403, but not the alpha4beta2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the alpha7 nAChR antagonists methyllycaconitine, alpha-bungarotoxin, and mecamylamine, but not by the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine. Increases in 3H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter 3H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Abeta and alpha7 nAChRs in the brain, suggesting that treatment with alpha7 nAChR stimulatory drugs can modulate Abeta/alpha7 nAChR pathogenic signaling mechanisms in AD brain.