Impact of Age-Related Clonal Hematopoiesis on Alzheimer's Disease - PROJECT SUMMARY / ABSTRACT The goal of this proposal is to establish whether age-related functional changes in peripheral immune cells influence Alzheimer's disease (AD) pathology onset and progression. While immune dysfunction is a hallmark of AD pathogenesis, peripheral-central nervous system crosstalk is not completely understood, creating a barrier to the development of new therapeutics for prevention or cure. The foundation of proper immune responses is the hematopoietic system's ability to produce well-functioning cells in correct proportions. Hematopoietic stem cells (HSCs), which produce all blood cells (including monocytes, neutrophils, T cells, and B cells), accumulate somatic mutations over their long lifetimes. Certain mutations provide a selective advantage that results in an increased expansion of those HSC “clones” and can lead to skewed proportions of and phenotypic changes in produced cell types. The incidence of this phenomenon, termed clonal hematopoiesis (CH), increases with age and is associated with higher risk of multiple diseases. Surprisingly, CH has been recently reported to be associated with decreased incidence of AD. To validate this association and propose an actionable mechanism for clinical disease intervention, we need to understand how mutations in peripheral immune cells impact the etiology and progression of AD. These studies necessitate mammalian models in which CH and AD proteinopathy are inducible in the same individual and blood and brain are available for examination prior to disease onset and throughout disease progression. Our research objective is to investigate the impact of Tet2 CH mutation on the ability of peripheral immune cells to infiltrate the brain and modulate AD pathology. To achieve our aims, we will introduce mutated cells into the circulation of well-defined AD mouse models. We will assess the effect of aging and proteinopathy development on the extent CH peripheral cell infiltration, identify and quantify infiltrating immune cells and their locations within the brain, determine whether circulating CH cells are increasingly primed for mobilization, and assess the effect of CH on AD pathology development. Determining that a CH mutation a) increases the immune cell infiltration into the brain, and b) leads to deceased pathology would provide a direct link between CH and AD and may nominate new candidates for therapeutic intervention for AD.
