Metabolic Reprogramming of Microglia in Alzheimer’s Disease
We will explore whether manipulation of a specific metabolic pathway in the brain’s primary immune cells (microglia) can protect against Alzheimer’s pathology.We will genetically inhibit a specific metabolic pathway in microglial cells and address three aims in two mouse models of Alzheimer’s disease pathology. Aim 1 will be to analyze pathological hallmarks, e.g. whether microglia can clear more amyloid plaques or can better shield the brain from their toxic effects. Aim 2 will be to assess which molecular pathways and functions of microglia are altered and may underly changes in pathological hallmarks. Aim 3 will test whether these changes in microglial responses are sufficient to preserve cognitive function in the mouse models.
We have found that a specific pathway in microglia can limit the cells’ beneficial functions in models of Alzheimer’s disease, but the underlying changes in microglial immune responses and functionality are unknown. We will test for the first time whether inhibition of this pathway can alleviate pathological hallmarks and improve the functional outcome in models of Alzheimer’s disease pathology. In this project, we will establish whether reprogramming metabolism in microglial cells is sufficient to improve brain function in Alzheimer’s disease. If this is the case, it will open up new therapeutic opportunities to combat this devastating condition.