Targeting metabolism to spur lethargic immune cells of the brain into clean up mode

What is it about?

The immune cells of the brain, microglia, lots of energy to clean up toxic waste that can otherwise build up in the brain and lead to Alzheimer’s disease. How is this fueled? We found that the translocator protein (TSPO) is critical for efficient energy production and waste clean-up by phagocytosis in mouse microglia. TSPO is commonly used in research to visualize inflammation in the living brain by positron emission tomography. But, what does TSPO tell us about inflammation in the Alzheimer’s brain? We found that TSPO levels were highest in the small number of microglia that are actively clearing toxic waste from the Alzheimer’s brain. Meanwhile, microglia lacking TSPO resembled damaged microglia observed in aging and Alzheimer’s disease. These damaged microglia burnt up sugar inefficiently, relying on glycolysis to produce energy. We show that this switch to glycolysis is controlled by binding of the key sugar-metabolizing enzyme, hexokinase-2, to the energy-producing part of the cell, the mitochondria. We developed a light-controlled strategy to remove the sugar metabolizing enzyme, hexokinase-2, from the mitochondria in living cells. Using this, we could ‘switch off’ glycolysis, which spurred lethargic microglia into clean-up mode. Importantly, we found that simply inactivating the sugar-metabolizing enzyme did not have the same benefit, indicating this enzyme carries out immune signaling functions when it is not busy generating energy. Previous studies have shown that levels of this sugar-metabolizing enzyme are increased in Alzheimer’s brains, and we found that exposure to toxic waste that builds up in the Alzheimer’s brain activates it in cultured microglia.

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Photo by Milad Fakurian on Unsplash

Photo by Milad Fakurian on Unsplash

Why is it important?

Alzheimer’s disease is the most common form of dementia with no cure. The immune cells of the brain called microglia tend to be damaged in people with the disease. This makes them less capable of clearing toxic waste that can build up and lead to Alzheimer’s disease. We found a way to spur microglia into action by reprogramming their metabolism. These findings set the stage for developing drugs that can specifically target metabolism in brain immune cells.