A study on the molecular mechanisms of neurodegeneration induced by high-mass amyloid-beta assembly, amylospheroids (ASPD)

高质量β淀粉样蛋白组装、淀粉样蛋白球体（ASPD）诱导神经退行性变的分子机制研究

• 批准号: 23390079
• 负责人: HOSHI Minako
• 金额: $ 12.56万
• 依托单位: Foundation for Biomedical Research and Innovation
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23390079/
• 关键词: 認知症; 神経細胞死; 構造異常; カルシウム; ミトコンドリア; タウ; アミロイド; シナプス

Amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). To elucidate the molecular identities of pathogenic Abeta oligomers and their neuronal targets responsible for neurodegeneration, we have previously isolated highly toxic Abeta assemblies termed amylospheroids (ASPD) from AD patient brains. Patient-derived ASPD were toxic to human mature neurons and their amount in AD susceptible regions well correlated with pathological severity of AD. In this study, we found that ASPD neurotoxicity requires Ca2+ influx. We also found that voltage gated calcium channels (VGCC) are involved in ASPD neurotoxicity. Interestingly, the abnormal Ca2+ overload induced by ASPD activated two tau protein kinases, and increased the phosphorylation of tau. Importantly, we found that ASPD-binding to the ASPD target protein on mature neuronal surface impairs its activity, responsible for the above abnormal Ca2+ homeostasis and to the severe neurodegeneration.

淀粉样β蛋白(Abeta)在阿尔茨海默病(AD)中起着核心作用。为了阐明致病的Abeta寡聚体及其导致神经变性的神经元靶点的分子身份，我们先前从AD患者的脑中分离出了称为淀粉球蛋白(ASPD)的高毒性Abeta组件。患者来源的ASPD对人成熟神经元具有毒性，其在AD易感区域的数量与AD的病理严重程度密切相关。在本研究中，我们发现ASPD的神经毒性需要钙离子内流。我们还发现电压门控钙通道(VGCC)参与了ASPD的神经毒性。有趣的是，ASPD引起的异常钙超载激活了两个tau蛋白激酶，并增加了tau的磷酸化。重要的是，我们发现，ASPD与成熟神经元表面的ASPD靶蛋白结合会损害其活性，导致上述钙稳态异常和严重的神经变性。

项目成果

A new toxic target for a high-mass amyloid β-protein assembly with a unique toxic structure

具有独特毒性结构的高质量β淀粉样蛋白组装体的新毒性靶点

• 发表时间: 2011
• 作者: Hoshi;M.;Ohnishi;T.;Inoue;M.;Hiroaki;H.;Nabeshima;Y.;Kakita;A
• 通讯作者: A

A NEUROTOXIC TARGET FOR AMYLOSPHEROID, A METHOD AND A MATERIAL FOR REDUCING THE NEUROTOXICITY OF AMYLOSPHEROID, AND A USE OF THE SAME

淀粉样蛋白球体的神经毒性靶标、降低淀粉样蛋白球体神经毒性的方法和材料及其用途

• 发表时间: 2012

A new toxic target for a high-mass amyloid ss-protein assembly with a unique toxic structure "International conference on Alzheimer's disease : Return to the Basics" at Annual meeting for Japanese Biochemical Societies, organized by Professors Iwata and H

具有独特毒性结构的高质量淀粉样蛋白 ss 蛋白组装体的新毒性靶标“阿尔茨海默病国际会议：回归基础”在日本生物化学会年会上，由岩田教授和 H 教授组织

• 发表时间: 2011
• 作者: Hoshi;M.;Ohnishi;T.;Inoue;M.;Hiroaki;H.;Nabeshima;Y.;Kakita;A.
• 通讯作者: A.

Involvement of the γ‐Secretase‐Mediated EphA4 Signaling Pathway in Synaptic Pathogenesis of Alzheimer's Disease

• DOI: 10.1111/j.1750-3639.2012.00587.x
• 发表时间: 2012-11
• 期刊: Brain Pathology
• 影响因子: 6.4
• 作者: C. Matsui;E. Inoue;A. Kakita;Kohei Arita;Maki Deguchi-Tawarada;A. Togawa;Akio Yamada;Y. Takai;H. Takahashi

Keap1 Is Localized in Neuronal and Glial Cytoplasmic Inclusions in Various Neurodegenerative Diseases

• DOI: 10.1097/nen.0b013e31827b5713
• 发表时间: 2013-01
• 期刊: Journal of Neuropathology & Experimental Neurology
• 影响因子: 3.2
• 作者: K. Tanji;Atsushi Maruyama;S. Odagiri;F. Mori;K. Itoh;A. Kakita;H. Takahashi;K. Wakabayashi