阿尔茨海默病（AD）是一种原发性进行性神经退行性疾病。前期研究表明，特异型Aβ异常蓄积和Tau过磷酸化可能与其发病密切相关，而维生素D（VitD）干预可显著提升脑Aβ清除速率，并改善个体认知功能及脑AD样损伤，但作用通路和靶点尚不明确；实验发现，丝裂原活化蛋白激酶（MAPKs）通路活性异常与神经退行性变及AD样损伤关系密切，但缺少基于其下游级联反应—MAPK活化蛋白激酶5（MK5）信号，与VitD干预和AD样变的关联研究。本项目拟通过建立AD动物和细胞模型，应用抑制剂处理和质粒转染/病毒载体技术（siRNA/shRNA），①验证pMK5/DJ1信号为AD（样变）干预的潜在靶点；合并VitD干预以②明确VitD致AD样变改善效应，考察pMAPKs/pMK5/DJ1信号在VitD调控过程中的介导作用，旨为VitD神经保护效应的探讨、AD发病机制探索及防治策略制定提供科学依据。

Alzheimer's disease is a primary progressive neurodegenerative disease. Though its pathogenesis is not clear, studies have linked it with the aberrant expression and extracellular accumulation of Aβs (or ADDLs, Amyloid beta-derived diffusible ligands), as well as the hyperphosphorylation of tau. In the meantime, 1,25-(OH)2-D3 intervention has been shown to improve learning and memory, and ameliorate AD-like pathologies, but the mechanism is yet to be elucidated. Furthermore, the mitogen-activated protein kinase (MAPKs) pathway plays an important role in nerve growth and development, axonal transport, and synaptic transmission/plasticity regulation, the abnormal activation of which has been reported to cause neurodegeneration. However, the relationship among MAPK kinase-activated protein kinase 5 (MAPKAPK5) signaling, vitamin D therapy and AD-like changes remained a mystery. Therefore, in vivo experiments will be performed in the current study (with transgenic mice and AAV-shRNA vectors), aiming to establish the relationship between AD-like pathologies with MK5 transductions (aberrant), and to illustrate the improvement effect of VitD on the learning and memory of the model mice, while investigating its association with the MK5 signaling; Meanwhile treatment with Aβ25-35 will be conducted in vitro, combined with intervene experiments of MAPKs inhibitors, plasmid transfections (siRNA) and 1,25-(OH)2-D3, aiming to investigate the role of pMAPKs/pMK5/DJ1 signaling in the process of VitD regulation. The results will provide a scientific basis for the exploration of pathogenesis of AD and the neuroprotective effect of VitD, as well as the treatment and prevention of AD.