Regulation of intracellular APP metabolism by phosphorylation

通过磷酸化调节细胞内 APP 代谢

• 批准号: 07457536
• 负责人: SUZUKI Toshiharu
• 金额: $ 3.65万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457536/
• 关键词: Alzheimer's Disease; amyloid precursor protein; beta-amyloid; protein phosphorylation; transcytosis; neuron; 遺伝子変異導入; 細胞生物学; 生化学; 分子生物学

beta-amyloid precursor protein (APP) containes three known phosphorylation sites in its cytoplasmic domain. We report here that phosphorylation of APP at Thr668, one of the three sites, is a neuron-specific phenomenon. In adult rat neuronal tissues and in primary cultures of rat hippocampal neuron, the phosphorylated form of APP (PiAPP) is localized in somatic plasma membrane and on neurites although APP distributes in somata and on neurites. Inhibition of axonal tranport results in complete disaappearance of PiAPP in primary cultures of rat hippocampal neuron, and disruption of transcytosis with brefeldin A altered the distribution of PiAPP in the neuron. Our findings indicate that APP is phosphorylated at the nerve terminal after fast axonal transport, and PiAPP is redistributed into plasma membrane and dendrites by transcytosis. Because the production of beta-amyloid (Abeta) is physiologically restricted to neuronal cells and because the phosphorylation of APP also is a neuronally specific event, analysis of the mechanism of APP phosphorylation may contribute to understanding the molecular mechanism of Ab production in Alzheimer's disease (AD).

β-淀粉样蛋白前体蛋白（APP）在其细胞质结构域中包含三个已知的磷酸化位点。我们在这里报告说，在这三个站点之一Thr668，App的磷酸化是一种神经元特异性现象。在成年大鼠神经元组织和大鼠海马神经元的原发性培养物中，APP（PIAPP）的磷酸化形式位于体细胞质膜和神经突在somata和神经突的神经突。轴突旋转的抑制作用导致PIAPP在大鼠海马神经元的原发性培养物中完全不明显，而用Brefeldin a跨胞症的破坏改变了神经元中Piapp的分布。我们的发现表明，快速轴突运输后在神经末端磷酸化，而PIAPP通过转胞膜重新分布在质膜和树突中。因为在生理上，β-淀粉样蛋白（ABETA）的产生仅限于神经元细胞，并且APP的磷酸化也是一个特定于神经元的事件，因此对APP磷酸化机制的分析可能有助于理解阿尔茨海默氏病（阿尔茨海默氏病）AB产生的分子机制（（广告）。

项目成果

Masaki Oishi, Angus C.Nairn, Andrew J.Czernik, Gloria S.Lim, Toshio Isohara, Samuel E.Gandy, Paul Greengard, and Toshiharu Suzuki: "The cytoplasmic domain of Alzheimer's amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult ra

Masaki Oishi、Angus C.Nairn、Andrew J.Czernik、Gloria S.Lim、Toshio Isohara、Samuel E.Gandy、Paul Greengard 和 Toshiharu Suzuki：“阿尔茨海默病淀粉样蛋白前体蛋白的胞质结构域在 Thr654、Ser655 处被磷酸化，并且

Toshiharu Suzuki: "Cause of Alzheimer's disease and drug development" BioClinica (in Japanese). 10(7). 56-59 (1995)

Toshiharu Suzuki：“阿尔茨海默病的病因和药物开发”BioClinica（日语）。

Suzuki,T.et al.: "Phosphorylation of Alzheimer′s β-amyloid precursor-like proteins" Biochemistry. (in press).

Suzuki, T. 等人：“阿尔茨海默病 β-淀粉样蛋白前体样蛋白的磷酸化”生物化学（出版中）。

Yasushi Satoh, Tatsunori Seki, Yutaka Kirino and Toshiharu Suzuki: "APP is phosphorylated specifically in brain tissues" Neurobiology of Aging. 17. 97-98 (1996)

Yasushi Satoh、Tatsunori Seki、Yutaka Kirino 和 Toshiharu Suzuki：“APP 在脑组织中特异性磷酸化”《衰老神经生物学》。

Toshiharu Suzuki: "Phosphorylation of Alzheimer's beta-amyloid protein precursor ; What is the physiological function of APP phosphorylation?" Neurobiology of Aging. 17. 81 (1996)

Toshiharu Suzuki：“阿尔茨海默病β-淀粉样蛋白前体的磷酸化；APP磷酸化的生理功能是什么？”