Involvement of P38MAPK activation by NMDA receptors and non-NMDA receptors in amyloid-β peptide-induced neuronal loss in rat hippocampal CA1 and CA3 subfields.

Oligomeric amyloid-β peptide (Aβ) has been found to be associated with the pathogenesis of Alzheimer's disease (AD). Numerous studies have reported Aβ neurotoxicity, but the underlying molecular mechanisms remain to be fully illuminated. In the present study, we investigated the Aβ-induced activation and regulation of P38MAPKs in rat hippocampus in vivo. The results showed that intracerebroventricular injection of oligomeric Aβ25-35 increased the activation (phosphorylation) of P38MAPKs, and the level of cleaved caspase-3, but decreased the number of neurons in rat hippocampal CA1 and CA3 subfields. Downregulation of P38MAPK activity by SB239063 protected against the Aβ neurotoxicity. Pretreatment with NMDA and non-NMDA receptor antagonists respectively suppressed P38MAPK activation induced by Aβ25-35 oligomers and presented neuroprotective effect. Taken together, these data suggest that P38MAPK activation via NMDA and non-NMDA receptors is a key signal cascade in Aβ-induced neuronal death. Inhibition of P38MAPK cascades may be a promising treatment in AD.