Phagocytosis and degradation of amyloid beta-protein by microglia in the brain of Alzheimer's disease

阿尔茨海默病大脑中小胶质细胞对淀粉样β蛋白的吞噬和降解

• 批准号: 08670743
• 负责人: AKIYAMA Haruhiko
• 金额: $ 1.41万
• 依托单位: Tokyo Institute of Psychiatry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670743/
• 关键词: Alzheimer's disease; amyloid beta-protein; microglia; phagocytosis; metabolism; アミロイドβ蛋白; アストロサイト; 分解処理; 抗体; エピトープ

Microglia and astrocytes sometimes contain granules immunopositive for amyloid beta-protein (Abeta) in brains of patients with Alzheimer's disease (AD). Although the significance of Abeta-containing glial cells has yet to be fully understood, overproduction of Abeta or failure in the degradative pathway of Abeta may induce such granular accumulation of Abeta in glial cells. Abeta removal from brain tissues is seen most typically in Alzheimer brain mwhich mis complicated with recent ischemia. In such lisions, Abeta deposits, together with necrotic tissue debris, are removed by infiltrating macrophages and reactive microglia. Abeta forms granules in the phagocytic cells. Abeta in these cells is N-terminally truncated around the alpha-secretase cleavage site.In the present study, we describe an uncommon form of diffuse Abeta deposits which is associated with many Abeta-containing glial cells. In these deposits, Abeta with the C-terminus of a residue valine^<40> (Abeta40) and Abeta with th … More e C-termini of alanine^<42>/threonine^<43> (Abeta42) coexist both extracellularly and intracellularly. The N-termini of Abeta in the extracellular diffuse deposits include aspartate^1, pyroglutamate^3, and pyroglutamate^<11>, among which pyroglutamate^3 staining is the most intense. Abeta in glial granules is N-terminally truncated around the alpha-secretase cleavage site. The diffuse Abeta deposits of this type are found only inconsistently and are absent in a number of cases examined in this study. It has to be noted, however, the neuropathological observation is always limited to a very small area of the entire brain. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Microglia and astrocytes in these Abeta deposit areas look quiescent compared with those associated with senile plaques and other lesions such as ischemia.Abeta secreted from neurons may be taken up by glial cells in its early, non-fibrous form. Within the glial cells proteolytic processing of Abeta takes place, with the C-terminal fragment being more slowly broken down than the N-terminal fragment. Such ready uptake would account for the lack of an inflammatory response to the Abeta. Despite their infrequency, the diffuse deposits described here may represent a very early stage of Abeta deposition. Abeta40, which is generally considered to deposit in the later stages of Abeta deposition, predominates in these deposits and may actually precede Abeta42 deposition. Association of Abeta containing glial cells with a presumably early stage of Abeta deposition infers the overproduction of Abeta or the impaired intraglial processing of Abeta in these areas. The results of this study also suggests that Abeta accumulates by continuous addition of newly produced Abeta. It suggests as well that significant removal of previously deposited Abeta can occur. Thus, there may be turnover of Abeta in every diffuse Abeta deposit. Less

阿尔茨海默病（AD）患者大脑中的小胶质细胞和星形胶质细胞有时含有淀粉样蛋白（Abeta）免疫阳性的颗粒。虽然含有Abeta的胶质细胞的意义尚未完全了解，但过量的Abeta生产或Abeta降解途径的失败可能会导致Abeta在胶质细胞中颗粒状积聚。脑组织中β细胞的移除最典型地出现在阿尔茨海默病合并近期缺血的脑组织中。在这种病变中，Abeta沉积物连同坏死组织碎片被浸润的巨噬细胞和反应性小胶质细胞清除。β在吞噬细胞中形成颗粒。这些细胞中的β在分泌酶切割位点周围被n端截断。在目前的研究中，我们描述了一种罕见形式的弥漫性β沉积，它与许多含有β的胶质细胞有关。在这些沉积物中，具有残基缬氨酸^<40> (Abeta40) c端的Abeta和具有残基缬氨酸^<42>/苏氨酸^<43> (Abeta42) c端的Abeta在细胞外和细胞内共存。胞外弥漫性沉积物中β蛋白n端包括天冬氨酸^1、焦谷氨酸^3和焦谷氨酸^<11>，其中焦谷氨酸^3染色最强烈。胶质颗粒中的β在分泌酶裂解位点周围被n端截断。这种类型的弥漫性β沉积只是不一致的，在本研究中检查的一些病例中没有发现。然而，必须指出的是，神经病理学观察总是局限于整个大脑的一个非常小的区域。补体活化在这些沉积物中并不突出，而且往往低于免疫组织化学检测的灵敏度。与老年斑和其他病变（如缺血）相关的区域相比，这些Abeta沉积区域的小胶质细胞和星形胶质细胞看起来是静止的。从神经元分泌的β可能在其早期非纤维形式被神经胶质细胞吸收。在胶质细胞内发生Abeta蛋白水解过程，c端片段比n端片段分解得更慢。这种快速吸收可以解释对β缺乏炎症反应的原因。尽管不常见，但这里描述的弥漫性沉积可能代表了Abeta沉积的非常早期阶段。Abeta40通常被认为沉积在Abeta沉积的后期，在这些沉积中占主导地位，实际上可能先于Abeta42沉积。含有β的胶质细胞与早期β沉积的关联推断出β的过量产生或这些区域内β加工受损。本研究结果还表明，Abeta是通过不断添加新产生的Abeta而积累的。这也表明，以前沉积的β可以发生显著的去除。因此，在每一个弥漫性β沉积中都可能有β的周转。少

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