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MBC in Press, published online ahead of print February 21, 2007
Mol. Biol. Cell 10.1091/mbc.E06-10-0975

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Submitted on November 1, 2006
Revised on January 26, 2007
Accepted on February 1, 2007

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; {dagger}Center for Advanced Biotechnology and Medicine and Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, NJ 08854

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 (fA{beta}). Primary mouse microglia can internalize fA{beta}, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fA{beta} 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 ~ 6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with MCSF or IL-6 acidify the lysosomes of microglia and enable them to degrade fA{beta}. Following treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH ~ 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 fA{beta} 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 fA{beta} degradation by microglia.

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






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