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

Abstract

Accumulation of the amyloid protein (Ab) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism by which Ab exerts its neurotoxic effect is largely unknown. It has been suggested that the peptide can bind to the a7 nicotinic acetylcholine receptor (a7nAChR). In this study, we examined the binding of Ab1-42 to endogenous and recombinantly expressed a7nAChRs. Ab1-42 did neither inhibit the specific binding of a7nAChR ligands to rat brain homogenate or slice preparations, nor did it influence the activity of a7nAChRs expressed in Xenopus oocytes. Similarly, Ab1-42 did not compete for a-bungarotoxin-binding sites on SH-SY5Y cells stably expressing a7nAChRs. The effect of the Ab1-42 on tau phosphorylation was also examined. Although Ab1-42 altered tau phosphorylation in a7nAChR-transfected SH-SY5Y cells, the effect of the peptide was unrelated to a7nAChR expression or activity. Binding studies using surface plasmon resonance indicated that the majority of the Ab bound to membrane lipid, rather than to a protein component. Fluorescence anisotropy experiments indicated that Ab may disrupt membrane lipid structure or fluidity. We conclude that the effects of Ab are unlikely to be mediated by direct binding to the a7nAChR. Instead, we speculate that Ab 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.

Role of Key Aromatic Residues in the Ligand-binding Domain of α7 Nicotinic Receptors in the Agonist Action of β-Amyloid

“…This is not surprising, as the agonist-binding site is fully contained within the ECD. On the other hand, oligomeric A␤ may still interact with the plasma membrane (18), perhaps specifically with receptor-associated lipid rafts (23).…”

“…Although direct assays for specific binding of A␤ on nAChRs are problematic (18), it was important to ask whether mutation of Tyr-188 affected the general interaction of A␤ with the receptor. Using coimmunoprecipitation (15), it was found that A␤ still associated with the Tyr-188S mutant of the ␣7-nAChR.…”

“…One possibility is the nicotinic acetylcholine receptor (nAChR), and A␤ regulation of nAChRs has been reported in numerous studies, most notably for the ␣7 subtype, but other subtypes have also been implicated (7,(12)(13)(14)(15). Homomeric nicotinic ␣7 nAChRs appeared to display high-affinity binding to A␤ (16,17), although this remains controversial (18). ␣7-nAChRs are highly expressed on the presynaptic inputs in the hippocampus and cortex, which are critical regions for synaptic plasticity and memory formation.…”

Molecular dynamics study of the interaction of Aβ(13-23) with β-sheet inhibitors

“…18,19 This region is also the binding site for cholesterol, 20 apolipoproteinE (apoE), 21 the α7 nicotinic acetylcholine receptor (α7nAChR), 22,23 and amyloid beta-peptide binding alcohol dehydrogenase (ABAD). 24 A model of the Aβ peptide consisting of amino acids 13-23 (Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)), was shown to initiate oligomerization. This region has been the basis for the synthesis of numerous small peptides as β−sheet blockers.…”

“…This region has been the basis for the synthesis of numerous small peptides as β−sheet blockers. 11,12,13,14,15 We also have used Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) as a model Aβ receptor, R = NAcH13H14Q15K16L17V18F19F20A21E22D23NHMe, for this purpose.…”