title: Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes.
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.
authors: Department of Biochemistry and Weill Cornell Medical College, New York, NY 10065, USA.
authors: Amitabha
authors: A
authors: Majumdar
authors: Estibaliz
authors: E
authors: Capetillo-Zarate
authors: Dana
authors: D
authors: Cruz
authors: Gunnar K
authors: GK
authors: Gouras
authors: Frederick R
authors: FR
authors: Maxfield
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007976:Leupeptins / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D061988:Proteasome Inhibitors; D021381:Protein Transport; D034622:RNA Interference; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D016229:Amyloid beta-Peptides; D018118:Chloride Channels; D007976:Leupeptins; D051907:Lysosomal Membrane Proteins; D016173:Macrophage Colony-Stimulating Factor; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; C490803:Clcn7 protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C509143:OSTM1 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde