Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 22, Issue 10, Pages 1664-1676Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E10-09-0745
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Funding
- National Institutes of Health [AG027140, R37DK27083]
- Appel Discovery grant
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Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid beta peptide (fA beta). 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 fA beta 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 fA beta degradation.
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