Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils.
Microglia are the main immune cells of the brain, and under some circumstances they can play an important role in removal of fibrillar Alzheimer amyloid beta peptide (fAbeta). Primary mouse microglia can internalize fAbeta, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fAbeta efficiently, and we found that microglia actually contain higher levels of many lysosomal proteases than macrophages. However, the microglial lysosomes are less acidic (average pH of approximately 6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with macrophage colony-stimulating factor (MCSF) or interleukin-6 acidify the lysosomes of microglia and enable them to degrade fAbeta. After treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH of approximately 5), and the MCSF-induced acidification can be partially reversed upon treatment with an inhibitor of protein kinase A or with an anion transport inhibitor. Microglia also degrade fAbeta if lysosomes are acidified by an ammonia pulse-wash or by treatment with forskolin, which activates protein kinase A. Our results indicate that regulated lysosomal acidification can potentiate fAbeta degradation by microglia.
Majumdar
Amitabha
A
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA.
Cruz
Dana
D
Asamoah
Nikiya
N
Buxbaum
Adina
A
Sohar
Istvan
I
Lobel
Peter
P
Maxfield
Frederick R
FR
D000544:Alzheimer Disease / Q000378:metabolism; D000643:Ammonium Chloride / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015850:Interleukin-6 / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015850:Interleukin-6; D000643:Ammonium Chloride; D016173:Macrophage Colony-Stimulating Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D010447:Peptide Hydrolases