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.
Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, China; School of Nursing, Xuzhou Medical College, Jiangsu, China.
Fang
F
Zhou
Yan
Y
Xu
Xiao-Yu
XY
Hou
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human
Alzheimer's disease; N-methyl-D-aspartate receptor; P38 mitogen-activated protein kinase; apoptosis; mixed-lineage kinase 3