MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAYS ARE INVOLVED IN REGULATING alpha 7 NICOTINIC ACETYLCHOLINE RECEPTOR-MEDIATED AMYLOID-beta UPTAKE IN SH-SY5Y CELLS

摘要

Intraneuronal accumulation of beta-amyloid protein (Ab) is an early pathological change in Alzheimer's disease (AD). Recent studies demonstrate that alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) binds to soluble A beta with a high affinity. In vitro and in vivo experiments also show that A beta activates p38 MAPK and ERK1/2 signaling pathways via the alpha 7nAChR. 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 alpha 7nAChR-mediated A beta uptake. However, the evidence for this hypothesis is lacking. In the present study, we examined whether A beta(1-42) oligomers activate MAPK signaling pathways via alpha 7nAChR, and assessed the role of MAPK signaling pathways in the regulation of A beta(1-42) uptake by alpha 7nAChR. We confirm that undifferentiated SH-SY5Y cells are capable of taking up extracellular A beta(1-42). The internalization of A beta(1-42) accumulates in the endosomes/lysosomes and mitochondria. MAPK signaling pathways are activated by A beta(1-42) via alpha 7nAChR. A beta(1-42) and alpha 7nAChR are co-localized in SH-SY5Y cells and the expression of a7nAChR involves in A beta(1-42) uptake and accumulation in SH-SY5Y cells. Our data demonstrate that A beta(1-42) induces an alpha 7nAChR-dependent pathway that relates to the activation of p38 MAPK and ERK1/2, resulting in internalization of A beta(1-42). Our findings suggest that alpha 7nAChR and MAPK signaling pathways play an important role in the uptake and accumulation of A beta(1-42) in SH-SY5Y cells. Blockade of alpha 7nAChR may have a beneficial effect by limiting intracellular accumulation of amyloid in AD brain and serves a potential therapeutic target for AD. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.