Investigation of molecular mechanisms for common diseases caused by aging and oxidative stress and development of drug candidates aiming the molecular targets

本课题旨在研究脂肪细胞产生脂肪细胞因子和小胶质细胞清除β-淀粉样肽的分子机制，为开发针对这些分子靶点的药物提供理论依据。在过去的三年中，我们获得了一些新的发现和候选药物如下。（1）ox-LDL通过翻译调节机制刺激机体产生包括脂肪细胞生长素在内的脂肪细胞因子。(2)We发现了寡聚β-淀粉样肽的新清除机制，其通过IL-4刺激在2型小胶质细胞中选择性诱导。（3）在转基因AD模型小鼠体内证实了其清除机制是诱导的。我们还发现，一些低分子量的化合物能够诱导清除机制。(4)We成功地产生了特异性单克隆抗体，以区分1型和2型小胶质细胞（专利申请）。上述所有结果都超出了我们的预期，特别是它们非常有希望创造出用于从阿尔茨海默病中恢复的新药。

In this project we aim to investigate the molecular mechanisms for adipocytokine production from adipocytes and clearance of β-amyloid peptide in microglia, which apply to develop drug candidates aiming the molecular targets. During the passed three years, we have obtained several novel findings and drug candidates as follows. (1)Production of some adipocytokines including resistin increased by stimulation of ox-LDL via translation modulated mechanism. (2)We found a novel clearance mechanism of oligomeric β-amyloid peptides, which is induced selectively in type-2 microglia by IL-4 stimulation. (3)The clearance mechanism was proved to induce in vivo using transgenic AD model mice. We also found that some compounds of low molecular weight are able to induce the clearance mechanism. (4)We are succeeded in generating specific monoclonal antibodies to discriminate type-1 and type-2 microglia (Patent is applied.)All the results described above are more than we expected, and they are very promising to create new drugs for recovering from Alzheimer's disease, in particular.