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Originally published as MBC in Press, 10.1091/mbc.E06-10-0975 on February 21, 2007

Vol. 18, Issue 4, 1490-1496, April 2007

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Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils

Amitabha Majumdar*, Dana Cruz*, Nikiya Asamoah*, Adina Buxbaum*, Istvan Sohar{dagger}, Peter Lobel{dagger}, and Frederick R. Maxfield*

*Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021; and {dagger}Center for Advanced Biotechnology and Medicine and Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, NJ 08854

Submitted November 1, 2006; Revised January 26, 2007; Accepted February 1, 2007
Monitoring Editor: Sandra Schmid

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 ~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 ~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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-10-0975) on February 21, 2007.

Address correspondence to: Frederick R. Maxfield (frmaxfie{at}med.cornell.edu)

Abbreviations used: DIDS, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid; fAbeta, fibrillar Alzheimer amyloid beta peptide; IL, interleukin; LPS, lipopolysaccharide; MCSF, macrophage colony-stimulating factor; PKA, protein kinase A.




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