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Investigation on the amyloid β-protein (Aβ)20231839

β淀粉样蛋白（Aβ）的研究20231839

基本信息

批准号：
10670618
负责人：
AKIYAMA Haruhiko
金额：
$ 1.73万
依托单位：
Tokyo Metropolitan Organization of Medical Research (1999-2000)Tokyo Institute of Psychiatry (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670618/
关键词：
Alzheimer's disease amyloid β-protein microglia Aβ-processing アミロイドβ蛋白

项目摘要

Microglia and astrocytes are sometimes found to contain granules immunopositive for in the brain tissues of patients with Alzheimer's disease(AD). To investigate the significance of such Aβ-containing glial cells, primary cultures of microglia and astrocytes from new borne rats were employed. Both microglia and astrocytes rapidly uptake Aβpeptides in culture medium. These cells accumulated Aβ intacellularly when they were cultured with μM to high nM Aβ1-42. Following elimination of Aβ from culture medium, Aβ granules gradually disappeared. Much higher concentration of Aβ1-40 was required for intracellular accumulation in microglia, indicating more effective clearance of Aβ1-40 than that of Aβ1-42. In mixed cultures of microglia and astrocytes, Aβ accumulated preferentially in microglia. Aβ uptake and intracellular accumulation in glial cells was also observed in in vivo experiments where Aβ was injected directly into the rat brain. In both in vitro and in vivo conditions, Aβ granules i … More n glial cells was 6E10(-)/4G8(+), indicating that processing of the amino-terminal portion of Aβoccurs similarly to human brain.Addition of fresh rat serum or rat anti-serum to Aβ to culture medium suppressed accumulation of Aβ in microglia. Injection of Aβ into the cisterna magna of the macrophage scavenger receptor (MSR) Knock-out mice resulted in the accumulation of Aβ in meningeal macrophages. Binding of Aβ to microglial plasma membrane was reported to be mediated by the HHQK sequence of Aβ(Aβ13-16). However, excess amounts of HHQK peptide failed to block accumulation of Aβ in microglia in both in vitro and in vivo expeeriments. These results indicate that Aβ uptake by microglia takes place through multiple pathways and that opsonization-mediated phagocytosis is not the major pathway.Aβ is produced continuously in the brain under physiological and pathological conditions. Except for rare cases of familial Alzheimer's disease (FAD), there is little evidence that prefers upregulation of Aβ production in the brain. Considering the effective uptake of Aβ by microglia, relative paucity of Aβ-containing glial cells in areas with a heavy Aβ-burden in the brain of AD should be an issue of intensive investigation. Less

有时发现阿尔茨海默病 (AD) 患者的脑组织中的小胶质细胞和星形胶质细胞含有免疫阳性的颗粒。为了研究这种含有 Aβ 的神经胶质细胞的重要性，使用了来自新生大鼠的小胶质细胞和星形胶质细胞的原代培养物。小胶质细胞和星形胶质细胞都快速摄取培养基中的 Aβ 肽。当这些细胞与 μM 至高 nM Aβ1-42 一起培养时，它们会在细胞内积累 Aβ。从培养基中消除 Aβ 后，Aβ 颗粒逐渐消失。小胶质细胞内积累需要更高浓度的 Aβ1-40，表明 Aβ1-40 比 Aβ1-42 更有效的清除。在小胶质细胞和星形胶质细胞的混合培养物中，Aβ优先在小胶质细胞中积累。在体内实验中，将 Aβ 直接注射到大鼠大脑中，也观察到神经胶质细胞中 Aβ 的摄取和细胞内积累。在体外和体内条件下，胶质细胞中的 Aβ 颗粒均为 6E10(-)/4G8(+)，表明 Aβ 氨基末端部分的加工过程与人脑相似。在 Aβ 培养基中添加新鲜大鼠血清或大鼠抗血清可抑制小胶质细胞中 Aβ 的积累。将 Aβ 注射到巨噬细胞清道夫受体 (MSR) 敲除小鼠的小脑延髓池中，导致 Aβ 在脑膜巨噬细胞中积聚。据报道，Aβ 与小胶质细胞质膜的结合是由 Aβ (Aβ13-16) 的 HHQK 序列介导的。然而，在体外和体内实验中，过量的 HHQK 肽均未能阻止小胶质细胞中 Aβ 的积累。这些结果表明，小胶质细胞对Aβ的摄取是通过多种途径进行的，调理介导的吞噬作用并不是主要途径。Aβ在生理和病理条件下在大脑中持续产生。除了罕见的家族性阿尔茨海默病 (FAD) 病例外，几乎没有证据表明大脑中 Aβ 的产生上调。考虑到小胶质细胞对 Aβ 的有效摄取，AD 大脑中 Aβ 负荷较重的区域中含有 Aβ 的神经胶质细胞相对较少，应该是深入研究的一个问题。较少的