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

阿尔茨海默病(AD)患者脑内的小胶质细胞和星形胶质细胞有时含有淀粉样β蛋白(Abeta)免疫阳性颗粒。虽然含有Abeta的神经胶质细胞的意义尚未完全被了解，但Abeta的过度生产或Abeta降解途径的失败可能会导致Abeta在神经胶质细胞中的颗粒状积聚。从脑组织中去除Aβ最常见的是阿尔茨海默病的大脑，这并不是最近的脑缺血。在这种炎症中，Abeta沉积和坏死的组织碎片一起被渗透到巨噬细胞和反应性小胶质细胞中清除。Abeta在吞噬细胞中形成颗粒。在这项研究中，我们描述了一种不常见的弥漫性Abeta沉积形式，它与许多含有Abeta的胶质细胞有关。在这些矿床中，具有残基缬氨酸的Abeta和具有Th…的Abeta更多的丙氨酸/苏氨酸(Abeta42)C末端同时存在于胞外和胞内。胞外弥漫性沉淀物中Abeta的N末端包括天冬氨酸^1、焦谷氨酸^3和焦谷氨酸^11&gt；，其中焦谷氨酸^3染色最深。神经胶质颗粒中的Abeta在α-分泌酶裂解部位的N端被截断。这种类型的弥漫性Abeta沉积只有在不一致的情况下才被发现，并且在本研究中检查的一些病例中不存在。然而，必须注意的是，神经病理观察总是局限于整个大脑的一个非常小的区域。这些沉积物中的补体激活并不明显，通常低于免疫组织化学检测的灵敏度。与老年斑和其他损伤(如缺血)相关的小胶质细胞和星形胶质细胞相比，这些沉积区域的小胶质细胞和星形胶质细胞看起来是静止的。神经元分泌的Abeta可能被早期的非纤维形式的胶质细胞摄取。在胶质细胞内，Abeta的蛋白分解过程发生，C-末端片段的分解速度比N-末端片段慢。这种现成的理解将解释对Abeta缺乏炎症反应的原因。尽管频率很低，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通常被认为是在Abeta42沉积的后期阶段沉积，在这些沉积中占主导地位，实际上可能先于Abeta42沉积。含有Abeta的胶质细胞与Abeta沉积的早期阶段相关联，推测这些区域Abeta的过度产生或Abeta的胶质内加工受损。这项研究的结果还表明，Abeta是通过不断增加新产生的Abeta而积累的。这也表明，先前沉积的Abeta可以发生显著的清除。因此，在每个弥漫性Abeta沉积中都可能存在Abeta的周转。较少

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