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Regulation of Microglial Lysosome Acidification

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Microglia are the main immune cells of the central nervous system. They normally carry out diverse functions, including removal of dead cells and other debris from the brain. Under some circumstances they have been shown to degrade Alzheimer’s disease amyloid plaques in acidic organelles called lysosomes. We have shown that the acidity of microglial lysosomes is controlled by signaling processes, and that resting microglia in cell culture are ineffective at degrading amyloid because of poor lysosome acidification. In this project we will use modern optical imaging methods to measure the acidity of microglial lysosomes in living mice. We will test the hypothesis that mechanisms to regulate acidity that we have observed in cell culture also operate in vivo. Our goal is to manipulate these signaling processes to regulate degradation of amyloid plaques and inflammatory activation of microglia.