Referenced in: none

Automatically associated channels: ClC4 , ClC7

Title: Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes.

Authors: Amitabha Majumdar, Estibaliz Capetillo-Zarate, Dana Cruz, Gunnar K Gouras, Frederick R Maxfield

Journal, date & volume: Mol. Biol. Cell, 2011 May 15 , 22, 1664-76

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21441306

Abstract
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.