Investigation on TGFbeta2 involvement in Alzheimer's disease's related neuronal death and Humanin signal transduction as an endogenous anti-Alzheimer's disease's defense factor

在我们早期的研究中，我们证明了TGF β 2是APP诱导阿尔茨海默病相关神经元死亡的假定天然配体（TGF β 2理论），Humanin可能是抑制阿尔茨海默病相关神经元死亡的特异性内源性神经保护多肽（防御理论）。该项目的第一个目的是获得证据支持阿尔茨海默病相关神经元细胞死亡的TGF β 2理论和阿尔茨海默病的防御理论。第二个目的是进行临床前研究，以开发Humanin或Humanin衍生物Colivelin作为阿尔茨海默病的神经保护药物。使用免疫组织化学和分子生物学技术，我们已经首次表明，TGF β 2的表达水平上调尸检阿尔茨海默病的情况下，在大脑中。此外，我们已经确定莫卡和POSH作为一个假定的介质连接PS1和TGF β 2触发的死亡信号通路。这些结果有力地支持了我们的TGF β 2理论。其次，我们鉴定了细胞膜上的Humanin受体，并阐明了除了JAK 2/STAT 3途径之外，Humanin还激活了PI 3激酶途径。在鉴定4k 1）和10 kD内源性Humanin样肽的基础上，我们现在还试图鉴定内源性Humanin样肽的一级结构。最后，我们已经成功地表明，Colivelin抑制阿尔茨海默病转基因小鼠模型Tg 2576小鼠年龄15个月的记忆障碍。所有这些结果表明Humanin或Humanin样肽作为内源性防御因子存在，并且Humanin的神经保护治疗可能对阿尔茨海默病有效。

In our earlier studies, we demonstrated that TGFbeta2 is a putative natural ligand of APP inducing Alzheimer's disease's related neuronal death (TGFbeta2 theory) and Humanin may be a specific endogenous neuroprotective polypeptide inhibiting Alzheimer's disease's relevant neuronal death (defense theory). The first purposes of this project have been to obtain evidence supporting the TGFbeta2 theory of Alzheimer's disease's related neuronal cell death and the defense theory of Alzheimer's disease. The second purpose has been to conduct preclinical research to develop Humanin or a Humanin's derivative Colivelin as neuroprotective drugs to Alzheimer's disease. Using immunohistochemistry and molecular biological techniques, we have first shown that TGFbeta2 expression levels were upregulated in brains of autopsied Alzheimer's disease cases. In addition, we have identified MOCA and POSH as a putative mediators linking PS1 and the TGFbeta2-triggered death signal pathway. These results strongly support our TGFbeta2 theory. Second, we identified a Humanin receptor on the cell membrane and elucidated that in addition to the JAK2/STAT3 pathway, a PI3 kinase pathway was activated by Humanin. Identifing 4k1) and 10kD endogenous Humanin-like peptides, we are also now trying to identify the primary structure of endogenous Humanin-like peptides. Finally, we have succeeded in showing that Colivelin inhibits memory impairment in Alzheimer's disease transgenic mouse models Tg2576 mice aged 15 months. All these results indicated that Humanin or Humanin-like peptides exist as an endogenous defense factor and that neuroprotective therapy with Humanin may be effective against Alzheimer's disease.