Functional Interactions of Fibrillar and Oligomeric Amyloid-β with Alpha7 Nicotinic Receptors in Alzheimer's Disease

Amyloid-beta (A beta) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that A beta binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and A beta pathogenesis. However, it is not yet known how the different A beta assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar A beta(1-40) is prevented through an alpha 7 nAChR-dependent mechanism. The alpha 7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [H-3] PIB to fibrillar A beta in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of A beta with alpha 7 nAChRs and prevent the formation of A beta/alpha 7 nAChR complexes. This interaction was confirmed in binding assays with [I-125] A beta(1-40) and alpha 7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of A beta fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca2+](i)) levels. Oligomeric, but not fibrillar A beta(1-40), increased [Ca2+](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar A beta exerts neurotoxic effects mediated partly through a blockade of alpha 7 nAChRs, whilst oligomeric A beta may act as a ligand activating alpha 7 nAChRs, thereby stimulating downstream signaling pathways.