Defining Region-Specific Microglia Endolysosomal Dysfunction and Neuro-Immune Crosstalk in Aging and Neurodegeneration

Microglia, the brain’s primary macrophages, play essential role in preserving neuronal homeostasis, clearing debris and shaping neural circuits throughout life. These functions are pivotal, particularly in context of aging and neurodegenerative diseases. Human genetic studies implicate microglia in age-related neurodegenerative diseases, with alterations in their endolysosomal network emerging as a critical determinant of disease risk. However, how microglial endolysosomal functions alter during aging and disease remain poorly defined, limiting our understanding of their contribution to disease pathology. This project employs cutting-edge in vivo TurboID proximity labelling proteomics tool to elucidate dynamic protein-protein interactions within Lamp1-associated cargoes in microglia and border-associated macrophages (BAMs). I will generate a high-resolution endolysosome-associated proteomic atlas of microglia and BAMs across distinct brain regions and ages. This atlas will identify proteomic changes and mechanisms that underpin neuroimmune dysfunction associated with aging and disease. By studying systemic and localized pathophysiological stressors, I aim to uncover compartment-specific disruptions in brain macrophages in vulnerable brain regions and their susceptibility to confer disease risk associated with aging and neurodegeneration. Using advanced spatial omics, computational tools, and functional in vivo and in vitro approaches in mice and human cells, I will define age- and region-specific microglia and BAM proteomic changes and map molecular microenvironments facilitating neuro-glia-immune crosstalk. This work addresses critical gaps in understanding microglial endolysosomal dysfunction and neuro-glia-immune crosstalk relevant to neurodegeneration. Resulting insights will revolutionize understanding of neuroimmune regulation and identify actionable immune molecular targets and biomarkers to inform the development of future therapeutic strategies.