Mechanisms of Aβ Clearance and Degradation by Glial Cells.
Mechanisms of Aβ Clearance and Degradation by Glial Cells.
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DOI：
10.3389/fnagi.2016.00160
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发表时间：
2016
影响因子：
4.8
通讯作者：
Sastre M
中科院分区：
文献类型：
--
作者：
Ries M;Sastre M
神经胶质细胞在脑中具有多种功能，范围从针对外部和内源性有害刺激的免疫防御、突触形成的调节、钙稳态和神经元的代谢支持。它们的失调可导致神经退行性疾病的发展，包括阿尔茨海默病（AD）。AD中胶质细胞最重要的功能之一是调节脑中淀粉样蛋白-β（Aβ）水平。据报道，小胶质细胞和星形胶质细胞作为Aβ清除和降解的调节剂发挥核心作用。神经胶质细胞降解Aβ的机制包括产生蛋白酶，包括脑啡肽酶（胰岛素降解酶）和内皮素转化酶，能够在不同的裂解位点水解Aβ。除这些酶外，其他蛋白酶也被描述在Aβ消除中发挥一定作用，如纤溶酶原激活剂、血管紧张素转换酶和基质金属蛋白酶。由神经胶质细胞释放的其他相关介质是细胞外分子伴侣，其单独参与Aβ的清除或与受体/转运蛋白联合参与A β的清除，从而促进A β进入血液循环。包括载脂蛋白、α 2-巨球蛋白和α1-抗胰凝乳蛋白酶。最后，星形胶质细胞和小胶质细胞在吞噬Aβ中具有重要作用，在许多情况下通过其表面上表达的许多受体。在这篇综述中，我们研究了所有这些机制，提供了在这一领域的最新研究的更新。
Glial cells have a variety of functions in the brain, ranging from immune defense against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer’s disease (AD). One of the most important functions of glial cells in AD is the regulation of Amyloid-β (Aβ) levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of Aβ clearance and degradation. The mechanisms of Aβ degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse Aβ at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in Aβ elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of Aβ alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, α2macroglobulin, and α1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing Aβ, in many cases via a number of receptors that are expressed on their surface. In this review, we examine all of these mechanisms, providing an update on the latest research in this field.