Metabolic Reprogramming of Microglia in Alzheimer’s Disease

About the Research Project
Program
Award Type
Standard
Award Amount
$289,650
Active Dates
July 01, 2021 - June 30, 2025
Grant ID
A2021035S
Goals
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 underlie changes in pathological hallmarks. Aim 3 will test whether these changes in microglial responses are sufficient to preserve cognitive function in the mouse models.
Summary
It is now clear that the brain’s immune system contributes significantly to the pathology of Alzheimer’s disease (AD). One recently appreciated role of microglia (the brain’s major immune cells) is to shield the brain from the damaging effects of amyloid-beta plaques – this is called the microglial ‘barrier function’. Importantly, genetic mutations that disrupt this microglial barrier lead to a strongly increased risk for developing AD. Therefore, ways to enhance this beneficial microglial function could provide novel therapeutic targets for AD. In preliminary work, we have identified a previously unknown molecular target whose genetic elimination leads to a significantly increased microglial barrier around amyloid plaques. In this project, we now aim to characterize the long-term effects of manipulating this molecular pathway in two independent animal models of AD pathology, with a particular focus on molecular and functional changes in microglia, pathological hallmarks of AD and most importantly, cognitive function. If successful, this work could lead to new treatment options for the devastating effects of Alzheimer’s disease.
Unique and Innovative
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.
Foreseeable Benefits
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.
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