Precision Targeting of Microglial Metabolism to Improve Neuronal Fitness and Cognition

Multiple sclerosis (MS) is the most common inflammatory disease of the brain, affecting more than 130,000 people in the UK alone. One of the most prevalent and debilitating symptoms of MS is cognitive impairment, which affects attention and memory. During their lifetime, more than half of people with MS will experience an accelerated ageing of the brain and develop disabling cognitive deficits, whose causes have yet to be fully elucidated. One of the possible drivers of brain damage and ageing in MS is the malfunctioning of microglia, the immune cells that reside in the brain and spinal cord. Normally, microglia function as the brain's clean-up crew by removing damaged cells and fine-tuning the activity of nerve cells (or neurons). However, recent data has shown that in MS, microglia become chronically overactive because of the way they produce and consume energy (i.e., their metabolism). This overactivity contributes to a persistent state of inflammation that may impede the correct functioning of neurons and their connections. With this research fellowship, I aim to test the hypothesis that specific metabolic pathways in microglia affect how these cells respond to and modulate the activity of surrounding neurons. By understanding how different microglial metabolic states affect brain functions, we will be able to develop new strategies to combat cognitive decline in MS and possibly other brain disorders. In this fellowship, I will focus on three key objectives: 1. Identify metabolic regulators of microglial activation. I will use a mouse model of MS-like disease to identify the metabolic factors that influence microglial activation in adult and aged mice. To do so, I will use a combination of brain imaging and pathological analysis to investigate how microglial and neuronal activation change in different brain regions during chronic inflammation. I will then study how microglial metabolism is correlated to changes in the functional connections between neurons and related cognitive dysfunction. 2. Understand the effects of modifying microglial metabolism to modulate neuronal functions. I will use 2D and 3D human cellular models to understand how manipulating precise metabolic pathways in microglia affects the function of human neurons grown with microglia in a dish. I will study metabolic pathways that I previously discovered in microglia, as well as new metabolic targets identified during the prior objective. This setup will establish a direct link between microglial metabolism and its effect on neuronal functionality. 3. Develop strategies to target microglial metabolism and slow cognitive decline. Based on the combined findings from the first two objectives, I will identify precise metabolic targets to modulate microglial activation in vivo. My goal will be to find new ways to reprogram microglia from their chronic, overactive, inflammatory state to acquire protective functions that will sustain proper neuronal fitness and slow down cognitive decline. While the journey toward effective treatments for cognitive impairment is still long, this research fellowship represents a novel step forward in our understanding of the mechanisms involved. By investigating the relationship between microglial metabolism and neurons, we may be able to develop drugs and interventions that can reduce chronic inflammation in the brain and protect its delicate functioning. Importantly, findings from this research will have broad applicability to other neurodegenerative diseases that are characterised by chronic inflammation and cognitive decline, such as Alzheimer's and Parkinson's diseases.