Mitogen-activated protein kinase signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor-mediated amyloid-β uptake in SH-SY5Y cells

W N Yang, K G Ma, X L Chen, L L Shi, G Bu, X D Hu, H Han, Y Liu, Y H Qian
Neuroscience 2014 October 10, 278: 276-90
Intraneuronal accumulation of beta-amyloid protein (Aβ) is an early pathological change in Alzheimer's disease (AD). Recent studies demonstrate that α7 nicotinic acetylcholine receptor (α7nAChR) binds to soluble Aβ with a high affinity. In vitro and in vivo experiments also show that Aβ activates p38 MAPK and ERK1/2 signaling pathways via the α7nAChR. Interestingly, it has been reported that p38 MAPK and ERK1/2 signaling pathways affect the regulation of receptor-mediated endocytosis. These data suggest that MAPK signaling pathways maybe involved in the regulation of α7nAChR-mediated Aβ uptake. However, the evidence for this hypothesis is lacking. In the present study, we examined whether Aβ1-42 oligomers activate MAPK signaling pathways via α7nAChR, and assessed the role of MAPK signaling pathways in the regulation of Aβ1-42 uptake by α7nAChR. We confirm that undifferentiated SH-SY5Y cells are capable of taking up extracellular Aβ1-42. The internalization of Aβ1-42 accumulates in the endosomes/lysosomes and mitochondria. MAPK signaling pathways are activated by Aβ1-42 via α7nAChR. Aβ1-42 and α7nAChR are co-localized in SH-SY5Y cells and the expression of α7nAChR involves in Aβ1-42 uptake and accumulation in SH-SY5Y cells. Our data demonstrate that Aβ1-42 induces an α7nAChR-dependent pathway that relates to the activation of p38 MAPK and ERK1/2, resulting in internalization of Aβ1-42. Our findings suggest that α7nAChR and MAPK signaling pathways play an important role in the uptake and accumulation of Aβ1-42 in SH-SY5Y cells. Blockade of α7nAChR may have a beneficial effect by limiting intracellular accumulation of amyloid in AD brain and serves a potential therapeutic target for AD.

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