Molecular mechanisms of cell death mediated by apolipoprotein E receptor family

研究目的：在以前的研究中，索赔人报告说，星形胶质细胞和小胶质细胞分泌的载脂蛋白E（ApoE）通过存在于神经元细胞表面的ApoE受体抑制神经元细胞死亡。在该通路中，磷酸化Tau蛋白的GSK-3β参与。因此，本研究从ApoE受体配体的差异来分析ApoE在细胞凋亡抑制功能和细胞内信号转导途径上的差异。结果：Reelin对维甲酸诱导的P19胚胎细胞神经元分化过程中的凋亡有保护作用。这种增加的存活率与磷脂酰肌醇-3-激酶（PI 3 K）/Akt途径的reelin活化相关。当用LY 294002抑制PI 3 K时，reelin未能保护免受这种视黄酸诱导的细胞凋亡。reelin的保护作用包括激活Src-家族激酶/PI 3 K/Akt通路，然后导致BAD在丝氨酸-136处的选择性磷酸化，而BAD的磷酸化缺陷突变（S136 A）抑制了这种保护作用。结论：这些研究定义了一种新的通路，其中reelin结合apoE受体，显著激活PI 3 K/Akt通路，导致BAD的磷酸化，这有助于保护细胞免于凋亡，从而在促进脑中成熟神经元的存活中起重要作用。

The purpose of the research :In former research, the claimants have reported that the apolipoprotein E(ApoE) which is secreted from the astrocytes and the microglias inhibit neuronal cell death through the ApoE receptors which exist in the neuronal cell surface. In the pathway, GSK-3β, which phosphorylates Tau protein, participated. Therefore, in this research, we analyze the difference of the apoptosis suppressing-function and in the intracellular signal transduction pathway by the difference of the ApoE receptor ligand. As the another ApoE receptor ligand, we deal with Reelin, this time.The result :Reelin protected P19 embryonal cells from apoptosis during retinoic-acid induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. When PI3K was inhibited with LY294002, reelin failed to protect against this retinoic-acid induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3K/Akt pathway which then led to selective phosphorylation of BAD at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection.The conclusion :These studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing thus serving an important role in promoting the survival of maturing neurons in the brain.