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

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. © 2014 Wiley Periodicals, Inc.