The role of peripheral versus brain myeloid immunity in the cognitive decline of aging and Alzheimer's disease

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The role of peripheral versus brain myeloid immunity in cognitive decline of aging and Alzheimer’s disease Aging is characterized by the development of detrimental immune responses, where sustained pro-inflammatory responses promote end-organ damage, including frailty, vascular disease, metabolic syndrome, and cancer. The brain is also highly vulnerable to aging, as demonstrated by the high prevalence of cognitive decline and Alzheimer’s disease (AD). The preponderance of myeloid loss-of-function variants in human genome-wide association studies (GWAS) had led to a focus on understanding the role of brain microglia in aging and in AD. However, the majority of myeloid cells exist outside of the brain, and the role of the peripheral myeloid compartment in the development of age- and AD-associated cognitive decline has not been formally tested. In this application, we will use novel approaches to test the role of the peripheral myeloid system and contrast that with the role of microglia in the development of cognitive decline associated with aging and accumulation of amyloid in preclinical murine models of aging and AD. We will test whether age-associated changes in the peripheral myeloid system alone are sufficient to promote cognitive decline, and conversely, whether microglial dysfunction alone can cause cognitive decline, independent of the peripheral myeloid system. To separate out the peripheral from brain myeloid systems, we will use a novel bone marrow transplantation approach and a complementary genetic strategy targeting microglia to compare the relative contributions of each myeloid compartment to age-associated cognitive decline and cognitive decline associated with accumulation of inflammatory amyloid-ß peptides. Using the TREM1 (Triggering Receptor Expressed on Myeloid cells-1) pathway as a representative, myeloid-specific pathway expressed in both compartments, we will parse out the relative contributions of peripheral myeloid cells versus brain microglia to age- and AD-associated cognitive decline and define immune-metabolic mechanisms of action underlying these contributions in Aims 1 and 2. In Aim 3, we will determine the function of TREM1-mediated immune responses in human myeloid cells. Understanding the relative contributions of the brain microglial vs peripheral myeloid compartments to age- and AD-associated cognitive decline will inform development of effective, disease-modifying therapies.