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Elucidation of the neurodegenerative mechanism induced by amylospheroid

淀粉样蛋白球体诱导的神经退行性机制的阐明

基本信息

批准号：
16500235
负责人：
HOSHI Minako
金额：
$ 2.37万
依托单位：
Mitsubishi Kagaku Institute of Life Sciences
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-16500235/
关键词：
neurodegeneration calcium Alzheimer's disease β-amyloid solvent environments self-organization 金コロイド

项目摘要

Oligomerization of β-amyloid (Aβ) has been hypothesized to initiate the pathogenic cascade of Alzheimer's disease (AD). Recent studies have shown that instead of fibrils, soluble oligomers are regarded as the substance of neurotoxicity, yet the physical and biochemical features of the toxic oligomers are still unclear. Among various Aβ oligomers including fibrils, we have previously identified and purified 10-15-nm spheres as the most toxic species in vitro, which we call amylospheroid (ASPD) (Hoshi et al. PNAS 2003). Recently we obtained the data suggesting the in vivo presence of ASPD (Noguchi, A., Matsumura, S., Hoshi, M., manuscript in preparation). These results raise the possibility that ASPD or ASPD-like molecule plays a potential role in the AD process. Therefore, elucidation of the ASPD formation will contribute to clarify which environments and how they induce the formation of the toxic Aβ oligomers in AD brains as well as to AD therapeutics.In this study, we have examined the chemical environments that promote ASPD formation and reasoned that ASPD formation is off the pathway to fibrils. It should be noted that in every conditions examined, neurotoxicity correlated solely with the formation of 10-15-nm ASPD. Furthermore, we addressed the question whether Aβ with familial mutations in its sequence, D7N-Aβ (Tottori) or E22G-Aβ (Arctic), forms ASPD as observed in the case of wild type Aβ. The neurotoxicity as well as the formation efficiency of ASPD derived from these mutants will also be presented (Noguchi, A., Hoshi, M., unpublished data). We also found that ASPD induced calcium influx in neurons which lead to calpain activation and co1comitant cell death (Kikuchi, S., Yanazawa, M., Hoshi, M., manuscript in preparation).

β-淀粉样蛋白（Aβ）的寡聚化已被假设启动阿尔茨海默病（AD）的致病级联反应。近年来的研究表明，可溶性低聚物代替原纤维被认为是神经毒性物质，但其毒性低聚物的物理生化特性尚不清楚。在包括原纤维在内的各种Aβ低聚物中，我们之前已经鉴定并纯化了10-15纳米的球体，作为体外毒性最强的物种，我们称之为淀粉球体（ASPD）（Hoshi等人）。PNAS 2003)。最近，我们获得了表明体内存在ASPD的数据（Noguchi， A., Matsumura， S., Hoshi， M.，手稿正在准备中）。这些结果提出了ASPD或ASPD样分子在AD过程中发挥潜在作用的可能性。因此，阐明ASPD的形成将有助于阐明哪些环境以及它们如何诱导AD大脑中毒性Aβ低聚物的形成以及AD的治疗方法。在这项研究中，我们研究了促进ASPD形成的化学环境，并推断ASPD的形成不在原纤维的途径上。值得注意的是，在每一种检查条件下，神经毒性仅与10-15纳米ASPD的形成相关。此外，我们还研究了在野生型Aβ中观察到的具有家族性序列突变的Aβ， D7N-Aβ (Tottori)或E22G-Aβ (Arctic)是否会形成反社会人格障碍。这些突变体的神经毒性以及ASPD的形成效率也将被提出（Noguchi， A., Hoshi， M.，未发表的数据）。我们还发现，ASPD诱导神经元钙内流，导致钙蛋白酶激活和伴随的细胞死亡（Kikuchi， S., Yanazawa， M., Hoshi， M.，论文正在准备中）。