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

Mol Biol Cell. 2011 May 15;22(10):1664-76. doi: 10.1091/mbc.E10-09-0745. Epub 2011 Mar 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Leupeptins / pharmacology
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism*
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism*
  • Proteasome Inhibitors
  • Protein Transport
  • RNA Interference


  • Amyloid beta-Peptides
  • Chloride Channels
  • Clcn7 protein, mouse
  • Lamp1 protein, mouse
  • Leupeptins
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Proteins
  • OSTM1 protein, mouse
  • Proteasome Inhibitors
  • Macrophage Colony-Stimulating Factor
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde