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

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Abstract
Accumulation of the amyloid protein (Aβ) in the brain is an important step in the pathogenesis of Alzheimer’s disease. However, the mechanism by which Aβ exerts its neurotoxic effect is largely unknown. It has been suggested that the peptide can bind to the α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we examined the binding of Aβ1-42 to endogenous and recombinantly expressed α7nAChRs. Aβ1-42 did neither inhibit the specific binding of α7nAChR ligands to rat brain homogenate or slice preparations, nor did it influence the activity of α7nAChRs expressed in Xenopus oocytes. Similarly, Aβ1-42 did not compete for α-bungarotoxin-binding sites on SH-SY5Y cells stably expressing α7nAChRs. The effect of the Aβ1-42 on tau phosphorylation was also examined. Although Aβ1-42 altered tau phosphorylation in α7nAChR-transfected SH-SY5Y cells, the effect of the peptide was unrelated to α7nAChR expression or activity. Binding studies using surface plasmon resonance indicated that the majority of the Aβ bound to membrane lipid, rather than to a protein component. Fluorescence anisotropy experiments indicated that Aβ may disrupt membrane lipid structure or fluidity. We conclude that the effects of Aβ are unlikely to be mediated by direct binding to the α7nAChR. Instead, we speculate that Aβ 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.

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