Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis.
Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis.
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DOI：
10.1523/jneurosci.5572-08.2009
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发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Landreth GE
中科院分区：
文献类型：
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作者：
Mandrekar S;Jiang Q;Lee CY;Koenigsknecht-Talboo J;Holtzman DM;Landreth GE
阿尔茨海默病的特征是β-淀粉样蛋白（Aβ）在脑实质内进行性沉积，并随后积累成老年斑。该疾病的发病机制与 Aβ 稳态的扰动以及这些可溶性和不溶性肽从大脑中的低效清除有关。据报道，小胶质细胞通过受体介导的吞噬作用介导纤维状 Aβ (fAβ) 的清除；然而，它们对可溶性 Aβ 肽 (sAβ) 清除的参与在很大程度上尚不清楚。我们报道，小胶质细胞通过不饱和的流体相巨胞饮机制从细胞外环境内化 sAβ，该机制与体外和体内的吞噬作用和受体介导的内吞作用不同。 sAβ 的摄取取决于肌动蛋白和微管蛋白动力学，不涉及网格蛋白组装、包被囊泡或膜胆固醇。内化后，荧光标记的 sAβ 共定位于胞饮小泡。小胶质细胞迅速将这些可溶性肽运输到晚期内溶酶体区室中，在那里它们被降解。此外，我们证明 sAβ 和 fAβ 的摄取主要通过不同的机制发生，并且在内化后被分离到单独的亚细胞囊泡区室中。值得注意的是，我们发现荧光标记的 sAβ 被蛋白水解降解后，荧光发色团被小胶质细胞保留。这些研究确定了小胶质细胞通过其从大脑中持续清除 sAβ 肽的能力参与维持 Aβ 稳态的重要机制。
Alzheimer's disease is characterized by the progressive deposition of β-amyloid (Aβ) within the brain parenchyma and its subsequent accumulation into senile plaques. Pathogenesis of the disease is associated with perturbations in Aβ homeostasis and the inefficient clearance of these soluble and insoluble peptides from the brain. Microglia have been reported to mediate the clearance of fibrillar Aβ (fAβ) through receptor-mediated phagocytosis; however, their participation in clearance of soluble Aβ peptides (sAβ) is largely unknown. We report that microglia internalize sAβ from the extracellular milieu through a nonsaturable, fluid phase macropinocytic mechanism that is distinct from phagocytosis and receptor-mediated endocytosis both in vitro and in vivo. The uptake of sAβ is dependent on both actin and tubulin dynamics and does not involve clathrin assembly, coated vesicles or membrane cholesterol. Upon internalization, fluorescently labeled sAβ colocalizes to pinocytic vesicles. Microglia rapidly traffic these soluble peptides into late endolysosomal compartments where they are subject to degradation. Additionally, we demonstrate that the uptake of sAβ and fAβ occurs largely through distinct mechanisms and upon internalization are segregated into separate subcellular vesicular compartments. Significantly, we found that upon proteolytic degradation of fluorescently labeled sAβ, the fluorescent chromophore is retained by the microglial cell. These studies identify an important mechanism through which microglial cells participate in the maintenance of Aβ homeostasis, through their capacity to constitutively clear sAβ peptides from the brain.