The β-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the α7 nicotinic acetylcholine receptor

Accumulation of the amyloid protein (A beta) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism by which A beta exerts its neurotoxic effect is largely unknown. It has been suggested that the peptide can bind to the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). In this study, we examined the binding of A beta 1-42 to endogenous and recombinantly expressed alpha 7nAChRs. A beta 1-42 did neither inhibit the specific binding of alpha 7nAChR ligands to rat brain homogenate or slice preparations, nor did it influence the activity of alpha 7nAChRs expressed in Xenopus oocytes. Similarly, A beta 1-42 did not compete for alpha-bungarotoxin-binding sites on SH-SY5Y cells stably expressing alpha 7nAChRs. The effect of the A beta 1-42 on tau phosphorylation was also examined. Although A beta 1-42 altered tau phosphorylation in alpha 7nAChR-transfected SH-SY5Y cells, the effect of the peptide was unrelated to alpha 7nAChR expression or activity. Binding studies using surface plasmon resonance indicated that the majority of the A beta bound to membrane lipid, rather than to a protein component. Fluorescence anisotropy experiments indicated that A beta may disrupt membrane lipid structure or fluidity. We conclude that the effects of A beta are unlikely to be mediated by direct binding to the alpha 7nAChR. Instead, we speculate that A beta may exert its effects by altering the packing of lipids within the plasma membrane, which could, in turn, influence the function of a variety of receptors and channels on the cell surface.