Referenced in: none

Automatically associated channels: Kv10.1

Title: MLK3-MKK3/6-P38MAPK cascades following N-methyl-D-aspartate receptor activation contributes to amyloid-β peptide-induced apoptosis in SH-SY5Y cells.

Authors: Fang Zhou, Yan Xu, Xiao-Yu Hou

Journal, date & volume: J. Neurosci. Res., 2014 Jun , 92, 808-17

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24482239

Abstract
Amyloid-β peptide (Aβ) has been implicated in the development of Alzheimer's disease (AD), but the underlying molecular mechanisms remain unclear. The present study explores the proapoptosis signaling evoked by N-methyl-D-aspartate (NMDA) receptors in Aβ neurotoxicity. Oligomeric Aβ25-35 incubation resulted in significant apoptosis of neuronal SH-SY5Y cells. Preadministration of the potent NMDA receptor antagonist MK801 promoted neuronal survival. Both NVP-AAM077 and Ro25-6981, GluN2A- and GluN2B-subunit-selective NMDA receptor antagonists, respectively, showed effects similar to those of MK801, supporting a critical role of GluN2A- or GluN2B-containing NMDA receptors in Aβ neurotoxicity. Exposure to oligomeric Aβ25-35 increased the phosphorylation (activation) of mixed-lineage kinase 3 (MLK3), dual-specific mitogen-activated protein kinase kinase 3/6 (MKK3/6), and P38 mitogen-activated protein kinase (P38MAPK) in SH-SY5Y cells. Inhibition of P38MAPK activation by SB239063 had a neuroprotective effect. K252a attenuated the phosphorylation of MLK3, MKK3/6, and P38MAPK but also partially prevented SH-SY5Y cells apoptosis. MK801, NVP-AAM077, and Ro25-6981, abrogated the MLK3-MKK3/6-P38MAPK activation induced by oligomeric Aβ25-35. These results suggest that the activation of GluN2A- or GluN2B-containing NMDA receptors is responsible for the activation of MLK3-MKK3/6-P38MAPK cascades, which contributes to Aβ-mediated cell apoptosis.