Molecular mechanisms of cell death mediated by apolipoprotein E receptor family

载脂蛋白E受体家族介导的细胞死亡的分子机制

• 批准号: 16601003
• 负责人: MITSUDA Moriaki
• 金额: $ 2.43万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16601003/
• 关键词: Apolipoprotein E receptor; Reelin; apoptosis

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.

研究目的：在以往的研究中，申请人报道了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。磷酸化 Tau 蛋白的 GSK-3β 参与了该通路。因此，本研究通过ApoE受体配体的不同来分析其凋亡抑制功能和细胞内信号转导途径的差异。作为另一种ApoE受体配体，我们这次选择了Reelin。结果：Reelin在视黄酸诱导的神经元分化过程中保护P19胚胎细胞免于凋亡。这种存活率的增加与磷脂酰肌醇 3 激酶 (PI3K)/Akt 途径的 reelin 激活有关。当 LY294002 抑制 PI3K 时，reelin 无法防止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/PI3K/Akt 通路，从而导致 BAD 在丝氨酸 136 处选择性磷酸化，而 BAD (S136A) 的磷酸化无能突变抑制了这种保护作用。结论：这些研究定义了一条新通路，其中 reelin 结合 apoE 受体，显着激活 PI3K/Akt 通路 引起 BAD 磷酸化，有助于保护细胞免于凋亡，从而在促进大脑中成熟神经元的存活中发挥重要作用。

项目成果

Dementia

• DOI: 10.1007/978-94-017-7509-0_61
• 发表时间: 2019
• 期刊: Neurourology
• 作者: M. A. Averbeck;Helmut Madersbacher

Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rbl, that upregulates Bcl-xL expression.

通过静脉输注人参皂苷（人参皂苷 Rbl）预防缺血性神经元死亡，该皂苷可上调 Bcl-xL 表达。

• 发表时间: 2006
• 期刊: J Cereb Blood Flow Metab. 26
• 作者: Zhang B;et al.
• 通讯作者: et al.

Prevention of Ischemic Neuronal Death by Intravenous Infusion of a Ginseng Saponin, Ginsenoside Rb1, That Upregulates Bcl-xL Expression

• DOI: 10.1038/sj.jcbfm.9600225
• 发表时间: 2006-05
• 期刊: Journal of Cerebral Blood Flow & Metabolism
• 影响因子: 6.3
• 作者: Bo Zhang;R. Hata;Pengxiang Zhu;Kohji Sato;T. Wen;Lihua Yang;H. Fujita;N. Mitsuda;Junya Tanaka;K. Samukawa;N. Maeda;M. Sakanaka

A novel alternative splice variant of nicastrin and its implication in Alzheimer disease

• DOI: 10.1016/j.lfs.2005.10.007
• 发表时间: 2006-04-18
• 期刊: LIFE SCIENCES
• 影响因子: 6.1
• 作者: Mitsuda, N;Yamagata, HD;Miki, T
• 通讯作者: Miki, T

L-Serine-mediated release of apolipoprotein E and lipids from microglial cells.

L-丝氨酸介导的小胶质细胞释放载脂蛋白 E 和脂质。

• 发表时间: 2004
• 期刊: Experimental Neurology 185
• 作者: Mori K;Yokoyama A;Yang L;Yang L;Maeda N;Mitsuda N;Tanaka J
• 通讯作者: Tanaka J