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.

Grant Number: 5R01AG070839-03
NIH Institute/Center: NIH
Principal Investigator: Katrin Andreasson