On Wednesday, Nov. 1, 2023 Nicholas Devanney successfully defended his dissertation and earned his doctoral degree in physiology. Congratulations Dr. Devanney!
Rewired metabolism in APOE4 microglia: Implications for inflammation and neurodegeneration
Among the earliest changes to occur in Alzheimer’s disease, metabolic dysfunction and chronic neuroinflammation are now known to be major driving forces in disease progression. The paradigm of ‘immunometabolism’ seeks to bridge these two facets, positing that metabolic transformations are indispensable in determining the response of immune cells, such as microglia – the brain’s resident immune population. Proinflammatory stimulation of microglia leads to a shift away from mitochondrial respiration towards a dramatic upregulation of the glycolysis pathway for energy production. This glycolytic burst provides microglia with a rapid supply of ATP, needed to fuel energy-intensive tasks such as rapid motility, proliferation, cytokine production, and phagocytosis. However, this comes at a cost, as utilizing glucose to produce energy via glycolysis is less efficient than mitochondrial respiration. Microglia thus must switch back to mitochondrial respiration and ramp down glycolysis in order to effectively respond to anti-inflammatory signals and restore the tissue to homeostasis. A breakdown in this process is evident in the genetics of late-onset Alzheimer’s disease (LOAD), as the majority of LOAD genetic risk factors are highly or specifically expressed in microglia. Many of these risk factors – including the strongest, the ε4 allele of apolipoprotein E (APOE4) - are thought to integrate metabolic inputs with downstream inflammatory signaling. APOE is the chief lipoprotein in the brain, responsible for trafficking lipids and thereby governing its bioenergetics. APOE4 microglia display a heightened production of pro-inflammatory cytokines coinciding with chronic neuroinflammation in APOE4 brains. This dissertation seeks to unify these two aspects of APOE4’s risk through the concept of immunometabolism. An integrative multi-omic approach enabled us to systematically dissect the role of APOE genotype in the microglial response to aging, inflammation, and amyloid pathology. In response to each of these challenges, a distinct metabolic response was revealed in APOE4 microglia, characterized by an increased reliance on glycolysis and impaired capacity to engage mitochondrial respiration. These changes were accompanied by alterations to the TCA cycle that altogether indicated a predisposition to pro-inflammatory immunometabolism in APOE4 microglia. Hypoxia-inducible factor 1α (HIF1α) was uncovered as driving mechanism behind not only this metabolic rewiring, but also having the potential to link APOE4 to downstream neurodegenerative phenotypes. Taken together, our findings point to a reprogramming of central metabolism according to APOE genotype such that APOE4 microglia are predisposed to pro-inflammatory and neurodegenerative pathways. Seeking to correct these metabolic impairments may represent a novel therapeutic avenue for the personalized treatment of Alzheimer’s disease.