title: Arctic mutant Aβ40 aggregates on α7 nicotinic acetylcholine receptors and inhibits their functions.
abstract: Amyloid β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Point mutations within the Aβ sequence associated with familial AD (FAD) are clustered around the central hydrophobic core of Aβ. Several types of mutations within the Aβ sequence have been identified, and the 'Arctic' mutation (E22G) has a purely cognitive phenotype typical of AD. Previous studies have shown that the primary result of the 'Arctic' mutation is increased formation of Aβ protofibrils. However, the molecular mechanism underlying this effect remains unknown. Aβ42 binds to a neuronal nicotinic acetylcholine receptor subunit, neuronal acetylcholine receptor subunit alpha-7 (CHRNA7), with high affinity and, thus, may be involved in the pathogenesis of AD. Therefore, to clarify the molecular mechanism of Arctic mutation-mediated FAD, we focused on CHRNA7 as a target molecule of Arctic Aβ. We performed an in vitro binding assay using purified CHRNA7 and synthetic Arctic Aβ40, and demonstrated that Arctic Aβ40 specifically bound to CHRNA7. The aggregation of Arctic Aβ40 was enhanced with the addition of CHRNA7. Furthermore, the function of CHRNA7 was detected by measuring Ca(2+) flux and phospho-p44/42 MAPK (ERK1/2) activation. Our results indicated that Arctic Aβ40 aggregation was enhanced by the addition of CHRNA7, which destabilized the function of CHRNA7 via inhibition of Ca(2+) responses and activation of ERK1/2. These findings indicate that Arctic Aβ mutation may be involved in the mechanism underlying FAD. This mechanism may involve binding and aggregation, leading to the inhibition of CHRNA7 functions.
authors: Faculty of Science and Engineering, Waseda University, Shinjuku, Tokyo, Japan.
authors: Ye
authors: Y
authors: Ju
authors: Toru
authors: T
authors: Asahi
authors: Naoya
authors: N
authors: Sawamura
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; D064569:alpha7 Nicotinic Acetylcholine Receptor; C078592:amyloid beta-protein (1-40); D002118:Calcium
keywords: Alzheimer's disease; amyloid; calcium; mitogen-activated protein kinases; nicotinic acetylcholine receptors