title: The beta-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the alpha7 nicotinic acetylcholine receptor.
abstract: Accumulation of the amyloid protein (Abeta) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism by which Abeta exerts its neurotoxic effect is largely unknown. It has been suggested that the peptide can bind to the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In this study, we examined the binding of Abeta1-42 to endogenous and recombinantly expressed alpha7nAChRs. Abeta1-42 did neither inhibit the specific binding of alpha7nAChR ligands to rat brain homogenate or slice preparations, nor did it influence the activity of alpha7nAChRs expressed in Xenopus oocytes. Similarly, Abeta1-42 did not compete for alpha-bungarotoxin-binding sites on SH-SY5Y cells stably expressing alpha7nAChRs. The effect of the Abeta1-42 on tau phosphorylation was also examined. Although Abeta1-42 altered tau phosphorylation in alpha7nAChR-transfected SH-SY5Y cells, the effect of the peptide was unrelated to alpha7nAChR expression or activity. Binding studies using surface plasmon resonance indicated that the majority of the Abeta bound to membrane lipid, rather than to a protein component. Fluorescence anisotropy experiments indicated that Abeta may disrupt membrane lipid structure or fluidity. We conclude that the effects of Abeta are unlikely to be mediated by direct binding to the alpha7nAChR. Instead, we speculate that Abeta 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia. david.small@med.monash.edu.au
authors.forename: David H
authors.initials: DH
authors.lastname: Small
authors.forename: Danuta
authors.initials: D
authors.lastname: Maksel
authors.forename: Megan L
authors.initials: ML
authors.lastname: Kerr
authors.forename: Judy
authors.initials: J
authors.lastname: Ng
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.forename: Cindy
authors.initials: C
authors.lastname: Chu
authors.forename: Hossein
authors.initials: H
authors.lastname: Mehrani
authors.forename: Sharon
authors.initials: S
authors.lastname: Unabia
authors.forename: Michael F
authors.initials: MF
authors.lastname: Azari
authors.forename: Richard
authors.initials: R
authors.lastname: Loiacono
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005454:Fluorescence Polarization; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D008563:Membrane Lipids; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins; C054634:methyllycaconitine; D000157:Aconitine