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Low-dose N-methyl-D-aspartate protects against amyloid-β-induced neurotoxicity by suppressing the MLK3-MKK7-JNK3
1Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, China.
Objective:
Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms.
Methods:
Primary rat cortical neurons were exposed to 10 μM Aβ25-35 to establish a neurotoxicity model. Neuronal apoptosis was assessed by 4',6-diamidino-2-phenylindole staining. The effects of low-dose NMDA (10 μM) on the PI3K-Akt and MLK3-MKK7-JNK3 signaling pathways were examined by immunoprecipitation and Western blotting. The PI3K inhibitor LY294002 was used to verify the role of PI3K signaling in NMDA-mediated regulation of the JNK3 pathway.
Results:
Low-dose NMDA (10 μM) significantly reduced 10 μM Aβ25-35-induced neuronal apoptosis. Mechanistically, NMDA reversed the Aβ-induced decrease in p-PDK1 and p-Akt levels and concurrently suppressed the activation of the MLK3-MKK7-JNK3 cascade. Moreover, treatment with LY294002 attenuated the inhibitory effect of NMDA on the MLK3-MKK7-JNK3 pathway.
Conclusion:
Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.