Xu Yan, Cao Da-Hong, Wu Gui-Mei, Hou Xiao-Yu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Jiangsu, China; Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Jiangsu, China; Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, China.
Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Jiangsu, China; Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, China.
Neurosci Res. 2014 Aug;85:51-7. doi: 10.1016/j.neures.2014.05.011. Epub 2014 Jun 11.
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.
寡聚淀粉样β肽（Aβ）已被发现与阿尔茨海默病（AD）的发病机制有关。众多研究报道了Aβ的神经毒性，但其潜在的分子机制仍有待充分阐明。在本研究中，我们在体内研究了Aβ诱导的大鼠海马中P38丝裂原活化蛋白激酶（P38MAPKs）的激活和调节。结果表明，脑室内注射寡聚Aβ25-35可增加P38MAPKs的激活（磷酸化）以及裂解的半胱天冬酶-3的水平，但会减少大鼠海马CA1和CA3亚区的神经元数量。SB239063下调P38MAPK活性可防止Aβ神经毒性。分别用N-甲基-D-天冬氨酸（NMDA）和非NMDA受体拮抗剂预处理可抑制Aβ25-35寡聚体诱导的P38MAPK激活，并呈现神经保护作用。综上所述，这些数据表明，通过NMDA和非NMDA受体激活P38MAPK是Aβ诱导神经元死亡的关键信号级联反应。抑制P38MAPK级联反应可能是AD的一种有前景的治疗方法。
