Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 110, Issue -, Pages 49-56Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2017.09.005
Keywords
Alzheimer's disease; Amyloid; Neuroprotection; MAP kinases; Nicotinic acetylcholine receptors
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Funding
- KAKENHI [15K06786]
- Center of Innovation Science and Technology based Radical Innovation and Entrepreneurship Program (COI STREAM) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan
- Grants-in-Aid for Scientific Research [15K06786] Funding Source: KAKEN
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Amyloid 13 protein (A beta) plays a central role in Alzheimer's disease (AD) pathogenesis. Point mutations in the A beta sequence, which cluster around the central hydrophobic core of the peptide, are associated with familial AD (FAD). Several mutations have been identified, with the Arctic mutation exhibiting a purely cognitive phenotype that is typical of AD. Our previous findings suggest that Arctic A beta 40 binds to and aggregates with CHRNA7, thereby inhibiting the calcium response and signaling pathways downstream of the receptor. Activation of CHRNA7 is neuroprotective both in vitro and in vivo. Therefore, in the present study, we investigated whether Arctic A beta 40 affects neuronal survival and/or death via CHRNA7. Using human neuroblastoma SH-SY5Y cells, we found that the neuroprotective function of CHRNA7 is blocked by CHRNA7 knockdown using RNA interference. Furthermore, Arctic A beta 40 blocked the neuroprotective effect of nicotine by inhibiting the ERK1/2 pathway downstream of CHRNA7. Moreover, we show that ERK1/2 activation mediates the neuroprotective effect of nicotine against oxidative stress. Collectively, our findings further our understanding of the molecular pathogenesis of Arctic FAD. (C) 2017 Elsevier Ltd. All rights reserved.
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