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Effects of membrane lipids on the incorporation of Alzheimer's β-amyloid protein into membranes and neurotoxicity

膜脂对阿尔茨海默病β-淀粉样蛋白掺入膜的影响和神经毒性

基本信息

批准号：
11672224
负责人：
KAWAHARA Masahiro
金额：
$ 1.98万
依托单位：
Tokyo Metropolitan Institute for Neuroscience
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

It is widely accepted that the neurotoxicity of β-amyloid protein (AβP) is implicated in the etiology of Alzheimer's disease. We have previously shown that AβP is directly incorporated into membranes, forms cation-selective ion channels, and causes an increase in intracellular calcium levels of immortalized hypothalamic neurons. We hypothesize that the disruption of calcium homeostasis through the unregulated amyloid channels may be the primary event of neuro-toxicity of AβP. In this study, we investigated the detailed characteristics of the increase in intracellular calcium levels of primary cultured rat hippocampal neurons caused by AβP using a multisite fluorometry system. We found and report here that AβP caused a marked increase in intracellular calcium levels of long-term (more than three weeks)-cultured rat hippocampal neurons, but not in short-term (less than 2 weeks)-cultured neurons. The responses of neurons to AβP were highly heterogeneous. Immunohistochemical observation revealed that some restricted neurons have an affinity to the AP. To determine the substances that can confer protection against the neurotoxicity of AβP, we preadministerated dehydroepiandrosterone sul-phate (DHEA-S), whose levels in the serum of elderly are reduced, and found a significant inhibition of the increase in intracellular calcium levels induced by AβP. Our results suggest the implication of the ability of AβP to form amyloid channels may be based on the Alzheimer's pathogenesis. It is also possible that the endogenous substances such as DHEA-S may con-tribute to the prevention from the neurotoxicity of AβP.

β-淀粉样蛋白（β-amyloid protein，AβP）的神经毒性与阿尔茨海默病的发病机制密切相关。我们以前已经证明，AβP直接掺入膜，形成阳离子选择性离子通道，并导致永生化下丘脑神经元细胞内钙水平升高。我们推测，通过不受调节的淀粉样蛋白通道破坏钙稳态可能是AβP神经毒性的主要事件。本研究采用多点荧光法研究了AβP引起原代培养大鼠海马神经元胞内钙离子浓度升高的详细特征。我们发现并报道，AβP可引起长期（3周以上）培养的大鼠海马神经元细胞内钙水平显著升高，但对短期（2周以下）培养的神经元无明显影响。神经元对AβP的反应具有高度异质性。免疫组织化学观察显示，部分限制性神经元与AP有亲和力。为了确定可以对抗AβP神经毒性的物质，我们预先给予硫酸脱氢表雄酮（DHEA-S），其在老年人血清中的水平降低，并发现显着抑制AβP诱导的细胞内钙水平升高。我们的结果提示AβP形成淀粉样蛋白通道的能力可能与阿尔茨海默病的发病机制有关。内源性物质如DHEA-S也可能对AβP的神经毒性起预防作用。