Arctic mutant Aβ40 aggregates on α7 nicotinic acetylcholine receptors and inhibits their functions

• Published in: Journal of Neurochemistry
• Main Authors: Ju, Ye, Asahi, Toru, Sawamura, Naoya
• Other Authors: KAKENHI, High-Tech Research Center, Consolidated Research Institute of Advanced Science and Medical Care, Global COE ‘Practical Chemical Wisdom’ projects, Waseda University, COI STREAM, Ministry of Education, Culture, Sports, Science and Technology
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2014
• Subjects: Cellular and Molecular Neuroscience; Biochemistry; Arctic
• Online Access: http://dx.doi.org/10.1111/jnc.12837; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fjnc.12837; https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.12837

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 ( CHRNA 7), 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 CHRNA 7 as a target molecule of Arctic Aβ. We performed an in vitro binding assay using purified CHRNA 7 and synthetic Arctic Aβ40, and demonstrated that Arctic Aβ40 specifically bound to CHRNA 7. The aggregation of Arctic Aβ40 was enhanced with the addition of CHRNA 7. Furthermore, the function of CHRNA 7 was detected by measuring Ca 2+ flux and phospho‐p44/42 MAPK ( ERK 1/2) activation. Our results indicated that Arctic Aβ40 aggregation was enhanced by the addition of CHRNA 7, which destabilized the function of CHRNA 7 via inhibition of Ca 2+ responses and activation of ERK 1/2. 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 CHRNA 7 functions. image Amyloid β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). The ‘Arctic’ mutation within the Aβ sequence has a purely cognitive phenotype typical of AD. Here, we show that Arctic Aβ40 aggregation was enhanced by the addition of neuronal acetylcholine receptor subunit alpha‐7 (CHRNA7), which destabilized CHRNA7 functions via inhibition of the ...