For over a decade, it has been known that amyloid β (Aβ) peptides of Alzheimer's disease bind to the nicotinic α7 acetylcholine receptor (AChR) with picomolar affinity, and that snake α-neurotoxins competitively inhibit this binding. Here we propose a model of the binding mechanism of Aβ peptides to α7-AChR at atomic level. The binding mechanism is based on sequence and structure similarities of Aβ residues with functional residues of snake α-neurotoxins (ATX) in complex with AChR. The binding mechanism involves residue AβK28 (similar to ATXR32) which forms cation/π interactions in the acetylcholine binding site, and residues AβG29-AβI32 [GAII] (similar to ATXG33-ATXI36 [GTII]) which form an intermolecular β-sheet with residues α7F189-α7E191 of AChR. Through these interactions, we propose that the AChR serves as a chaperone for Aβ conformational changes from α- to β-hairpin. The interactions which block channel opening provide fundamental insight into Aβ neurotoxicity and cognition impairment, that could contribute to pathogenic processes in Alzheimer's disease, thus paving the way for structure based therapies.
Bibliographical noteFunding Information:
This research was supported by the Katz foundation and Marie-Curie CIG grant 322113 to AS.
- Acetylcholine receptor
- Alzheimer's disease
- Nicotinic acetylcholine receptor
- Snake toxin