Wednesday, April 2, 2025
4/2/2025
Reprogramming myeloid cell metabolism to prevent cognitive aging and Alzheimer's Disease - REPROGRAMMING MYELOID CELL METABOLISM TO PREVENT COGNITIVE AGING AND ALZHEIMER’S DISEASE SUMMARY The brain is highly vulnerable to aging, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease (AD). Human genome-wide association studies demonstrate a dominant role for dysfunctional myeloid cells, which include brain microglia as well as peripheral monocytes/macrophages (Mo/Mph), in increasing risk of AD. Microglia lose their normal capacities to maintain immune homeostasis within the brain, provide trophic support to neurons, and clear misfolded proteins. Circulating factors in aged plasma influence microglial activation and are linked to age-associated cognitive decline. These observations point to a causal role of brain and/or systemic myeloid dysfunction in development of cognitive decline in aging and AD. In our recent studies, we have identified an important role for cellular bioenergetics in regulating immune responses in aging macrophages and microglia. Maintenance of homeostatic and healthy immune function requires robust glycolytic and mitochondrial metabolism to meet demand for energy and biosynthetic precursors. Indeed, our recent studies demonstrate that glycolysis and mitochondrial respiration are significantly suppressed in aging microglia and Mo/Mph, leading to an energy deficient state that promotes maladaptive pro-inflammatory responses and decreased phagocytic potential. In this proposal we will test whether reprogramming cellular metabolism in aging microglia and/or peripheral Mo/Mph by modulating a major inflammatory pathway, the PGE2 signaling pathway, is disease-modifying in aging and in AD model mice. There is a growing literature on how cellular metabolism regulates immune cell function, particularly in the areas of infection and cancer. This conceptual framework has not yet been applied to aging, nor has it been applied to cognitive aging and age- associated neurodegenerative diseases like AD. Our approach proposed here will answer several fundamental questions including: (1) whether myeloid metabolic deficits drive brain aging, (2) whether peripheral or brain myeloid compartments are critical in this process, and (3) whether targeting myeloid metabolism represents a new therapeutic approach for AD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).