Sunday, May 11, 2025
5/11/2025
The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease - PROJECT SUMMARY Recent progress has been made on understanding the role of the innate immune system in the pathogenesis of Alzheimer’s disease (AD); however, the role of adaptive immunity in the periphery and the central nervous system in AD remains largely unexplored. Therefore, a critical next step is to understand the interaction between innate and adaptive immunity, and its impact on brain aging and neurodegeneration. Previous work has shown that clonally expanded CD8+ T cells are present in the peripheral blood and the cerebrospinal fluid of patients with AD. In our ongoing work, utilizing single cell profiling of human brain immune cells, we expanded this observation and identified cell type changes of the adaptive and innate immune system in the brain parenchyma of AD derived samples. In addition, published and ongoing work from our group provides evidence in humans and mice that astrocyte and adaptive immune cell-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Further analysis of the interaction between innate and adaptive immunity in humans and mice is needed to mechanistically understand its role in AD at different stages of the disease. Studying the interaction between innate and adaptive immunity in AD in humans is challenging due to limited availability of fresh tissue specimens. Over the last 5 years, our team has established a pipeline to isolate immune cells from fresh brain tissue to generate multiscale single cell data. Building on our expertise and existing resources, here we propose to perform multi-tissue single cell multiomics and spatial transcriptomics of immune cells from AD cases and healthy controls. To gain additional mechanistic insights into the interactions between adaptive and innate immunity, we will perform parallel studies in AD mouse models. In Aim 1, we will examine the diversity, abundance and spatial location of adaptive and innate immune cells across the brain-barrier-blood axis (brain, meninges, choroid plexus, and peripheral blood) to identify differences in the composition, phenotype, and antigen specificity of adaptive immunity (T and B cells) in AD that are shared or distinct across tissues. In Aim 2, we will explore the interactome of adaptive and innate immune systems in the brain-barrier-blood axis to identify differential cell-to-cell interaction networks in AD, pointing to gain or loss of ligand-receptor relationships among immune cell subpopulations. In Aim 3, we will mechanistically delineate intercellular crosstalk between adaptive immune cells and central innate immune cells in murine models of AD. Collectively, these studies will enable us, at unprecedented resolution, to explore the adaptive and innate immune response in AD cases and provide a putative mechanistic explanation for our observations by utilizing mouse models. Importantly, our work will provide the scientific community with an urgently needed resource for adaptive and innate immunity in the central nervous system that can be utilized in future studies.
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