Regulation of Microglial Lysosome Acidification

2016, 2017, 2019

Microglial cells are the scavenger cells of the brain responsible for clearance of dead cells, denatured proteins and other debris. We have studied the ability of microglial cells isolated from the brains of newborn mice to degrade the amyloid beta that accumulates in the brains of Alzheimer’s patients. We found that microglia could take up small particles of amyloid beta efficiently and deliver them to lysosomes—the digestive organelles of cells. However, the microglia in our cell culture experiments were unable to degrade the amyloid beta even though it was in the lysosomes. We found the reason for poor degradation was that the lysosomes in microglia were not as acidic as lysosomes in other cells. The digestive enzymes in lysosomes require acid conditions for their activity. Treatments that activated the microglia led to good acidification and rapid degradation of internalized amyloid beta.

The goal of this project is to determine whether the same lysosomal pH regulation occurs in vivo. We have verified that the fluorescent dextran injected into the upper spinal cord can diffuse into the brain and be taken up by the microglia in a living mouse. We image the cells in the brain using a method called multiphoton microscopy, which allows us to see detailed images relatively deep in a mouse brain. We will begin to measure the effects of increased lysosome acidification on degradation of amyloid plaques. We believe this regulation of the degradative capacity of microglia is a potential site of therapeutic regulation.

 


Funding to Date

$420,006

Focus

Foundational Genetics, Immune System Structures, Translational Research

Researchers

Frederick Maxfield, Ph.D.