Investigation on the amyloid β-protein (Aβ)20231839

在阿尔茨海默病（AD）患者的脑组织中，有时发现小胶质细胞和星形胶质细胞含有免疫阳性颗粒。采用新生大鼠小胶质细胞和星形胶质细胞原代培养，探讨含a β胶质细胞的意义。小胶质细胞和星形胶质细胞在培养基中均能快速摄取a β肽。在高nM Aβ1-42的μM培养下，这些细胞在细胞内积累了Aβ。从培养基中去除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混合培养中，Aβ优先在小胶质细胞中积累。在体内实验中，将Aβ直接注射到大鼠脑内，也观察到Aβ在胶质细胞中的摄取和细胞内积累。在体外和体内条件下，Aβ颗粒在神经胶质细胞中的比例为6E10(-)/4G8(+)，表明Aβ氨基末端的加工过程与人脑相似。在培养液中加入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注射到巨噬细胞清除受体（MSR）敲除小鼠的大池中，导致Aβ在脑膜巨噬细胞中积累。据报道，Aβ与小胶质质膜的结合是由Aβ的HHQK序列（Aβ13-16）介导的。然而，在体外和体内实验中，过量的HHQK肽未能阻止Aβ在小胶质细胞中的积累。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，而调理介导的吞噬不是主要途径。在生理和病理条件下，Aβ在大脑中不断产生。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产生的上调。考虑到小胶质细胞对a β的有效摄取，AD患者大脑中a β负荷较重的区域中含有a β的胶质细胞的相对缺乏应该是一个深入研究的问题。少

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