Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes.
Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes.
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DOI：
10.1091/mbc.e10-09-0745
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发表时间：
2011-05-15
影响因子：
3.3
通讯作者：
Maxfield FR
中科院分区：
文献类型：
--
作者：
Majumdar A;Capetillo-Zarate E;Cruz D;Gouras GK;Maxfield FR
Microglial lysosomes lack ClC-7, which leads to incomplete lysosomal acidification. In quiescent microglia, ClC-7 is targeted for proteasomal degradation apparently by an endoplasmic reticulum-associated degradation (ERAD) pathway. Microglial activation recruits ClC-7 to lysosomes and causes lysosomal acidification, which leads to efficient amyloid degradation. Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum–associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAβ degradation.
