Search for neuronal cell death-inhibiting drugs for Alzheimer's disease-relevant signal transduction

寻找用于阿尔茨海默病相关信号转导的神经元细胞死亡抑制药物

• 批准号: 22590247
• 负责人: HASHIMOTO Yuuichi
• 金额: $ 2.91万
• 依托单位: Tokyo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590247/
• 关键词: アルツハイマー病; 神経細胞死; アミロイド前駆体蛋白質; プレセニリン; ヒューマニン; アミロイド前駆体タンパク質; 神経変性疾患; サイトカイン; 細胞内シグナル伝達; 受容体; 治療薬; 細胞内シグナル伝

In this research program, we have examined the neuronal cell death mechanism underlysing Alzhemer’s disease (AD), and identified an antagonist of Humanin (HN) which inhibited AD-relevant neuronal cell death and an endogenous agonist of HN receoptor complex composed of WSX-1, ciliary neurotrophic factor receptor/gp130. The results were: (1) MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal, (2) V-set transmembrane domain containing 2 like inhibited HN’s activity via direct binding, and (3) A series of experiments also showed that calmodulin-like skin protein (CLSP), highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. CLSP inhibited familial AD-linked V642I-APP-induced neuronal cell death via its binding to HN receptor following activation of JAK2/STAT3 axisThese results suggest that CLSP play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.

本研究旨在探讨阿尔茨海默病（Alzhemer 'sdisease，AD）的神经细胞死亡机制，并鉴定了一种抑制AD相关神经细胞死亡的Humanin（HN）拮抗剂和一种HN受体复合物的内源性激动剂，该复合物由睫状神经营养因子受体（Ciliary Neurotrophic Factor Receptor，WSX-1）/gp 130组成。结果是：（1）莫卡是将APP介导的死亡信号统一为PS介导的死亡信号的关键分子;（2）含有V-set跨膜结构域的2 like通过直接结合抑制HN的活性;（3）一系列实验还表明，在皮肤组织中高表达的钙调素样皮肤蛋白（calmodulin-like skin protein，CLSP）通过血脑屏障转运到中枢神经系统。CLSP通过激活JAK 2/STAT 3轴与HN受体结合抑制家族性AD连锁的V642 I-APP诱导的神经元细胞死亡。这些结果表明，CLSP作为一种生理防御因子在体内抑制AD相关的神经元死亡和功能障碍中发挥主要作用。

项目成果

TAG-1 in an inhibitor of TGFβ2-induced neuronal cell death via amyloid β precursor protein

TAG-1 通过淀粉样蛋白 β 前体蛋白抑制 TGFβ2 诱导的神经元细胞死亡

• 发表时间: 2010
• 期刊: Biochemical and Biophysical Research Communications
• 影响因子: 3.1
• 作者: Tachi;N.;Hashimoto;Y.;et al
• 通讯作者: et al

VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin

• DOI: 10.1096/fj.10-163535
• 发表时间: 2011-06-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Rossini, Lara;Hashimoto, Yuichi;Caricasole, Andrea
• 通讯作者: Caricasole, Andrea

Involvement of MOCA in Alzheimer ' s disease-relevant neuronal cell death via APP and presenilins

MOCA通过APP和早老素参与阿尔茨海默病相关的神经元细胞死亡

• 发表时间: 2011
• 作者: Hashimoto Y;Tachi N;Matsuoka M
• 通讯作者: Matsuoka M

Involvement of MOCA in neuronal cell death triggered by familial Alzheimer's disease-linked mutants of APP and presenilins.

MOCA 参与由家族性阿尔茨海默病相关的 APP 和早老素突变体引发的神经细胞死亡。

• 发表时间: 2011
• 作者: 橋本祐一;太知信之;名和幹朗;松岡正明
• 通讯作者: 松岡正明

SH3BP5 is essential for Humanin-mediated protection against Alzheimer's disease-relevant toxicity

SH3BP5 对于护脑素介导的针对阿尔茨海默病相关毒性的保护至关重要

• 发表时间: 2013
• 作者: 竹下裕二;橋本祐一;内野博之;松岡正明
• 通讯作者: 松岡正明