Microglia, the brain’s innate immune cells, remain one of the least understood cell populations of the brain. However, a series of recent discoveries has challenged several central dogmas of microglia biology and has revolutionized our knowledge of these cells. Microglia are no longer viewed as a progeny of monocytes, and are not simple bystanders of the diseases of the Central Nervous System (CNS); rather, they play a contributing role as the mediators of injury, inflammation, and neurodegeneration. Several Alzheimer’s disease (AD)-susceptibility genome-wide association studies (GWAS) implicate these cells as central to AD pathology and suggest that microglia have an active role in promoting disease severity and progression. However, at present, there is still uncertainty regarding the protective or deleterious role of microglia and how they contribute to different diseases.
Our recent work using single-cell mass cytometry (CyTOF) has challenged the restrictive one-microglial population view by identifying distinct CNS myeloid populations with different effector functions in neuroinflammatory and neurodegenerative disease models. This discovery reveals that heterogeneity is an invaluable tool for targeted interventions in diseases of the CNS.
In this emergent field of investigation, research in the Ajami Laboratory aims to determine the unique biological properties and function of each microglia subtype in different contexts of health and disease. In particular, our research is focused on understanding microglia’s relationship to the pathology of various neurological disorders, such as Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, Lewy body dementia and Alzheimer’s disease.
Using genetically engineered mouse models as well as human samples in combination with technological advancements such as single-cell technologies, we aim to understand the mechanisms that control the development and functional identity of each microglia subtype during homeostasis, and examine how these regulations are altered in different neurological diseases. We are seeking to identify dysregulated pathways in microglia and blood-derived macrophages, and determine how they contribute to different pathology in order for them to be harnessed for the treatment of different neurological disorders. We are additionally investigating the communication between microglia and peripheral immune cells and how this communication contributes to the onset and progression of several neurological disorders. Ultimately, we aim to identify specific therapeutic targets that will allow for disease modifying strategies aimed at neuroinflammation in an intelligent way without the risk of targeting the body’s entire immune system.