Metabolic Reprogramming of Microglia in Alzheimer's Disease: The Role of Lactate in Tau Pathology and Neuroinflammation

Abstract The goal of this proposal is to understand how shifts in microglial metabolism impact the progression of Alzheimer’s disease (AD) and whether targeting metabolic flux is efficacious for treating AD. Work from our group and others now illustrates that alterations in glucose metabolism are central to Alzheimer’s disease. While regional hypometabolism is a hallmark of later stage neurodegeneration, recent studies suggest subtle shifts in metabolism occur much earlier in AD. FDG-PET neuroimaging is the gold standard for assessing brain glucose uptake in AD yet lacks the sensitivity to detect cell specific changes or the fate of glucose following cellular uptake. This causes a fundamental gap in our knowledge regarding early-stage changes in metabolism, what cell types drive these changes, and whether these changes are protective or damaging to the brain. We hypothesize that early metabolic adaptations in AD are driven by microglial activation, causing increased glucose uptake and shifts in glucose utilization toward a more glycolytic profile. Lactate is the metabolic end product of glycolysis and is produced in excess during shifts from oxidative metabolism to glycolysis. Our preliminary data shows that brain and interstitial fluid (ISF) lactate is chronically elevated in mice with neurofibrillary tangles (e.g. P301S PS19 mice) and amyloid plaques (e.g. APP/PS1 mice). We found ISF lactate increases in response to proinflammatory stimuli, like LPS. We found that genes responsible for lactate production (Ldha) and lactate consumption (Ldhb) are highly expressed in microglia, and upregulated in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs) expressing the MAPT IVS10+16 mutation; a mutation associated with tau accumulation. We also found a pharmacological approach to block lactate metabolism with stiripentol, an inhibitor of lactate dehydrogenase (LDH) activity, which reduces ISF lactate and ISF Aβ levels by 50%. However, we do not know how reactive microglia, lactate, and tau pathology interrelate and whether modulating LDH activity or lactate levels will reduce ISF tau levels or tau aggregation. Together, this suggests that tau aggregation leads to excess lactate production which we hypothesize is due to changes in microglial metabolism and function. In this proposal, we will determine the relative contribution of microglia to glucose metabolism, lactate production, and metabolic flux. Next, we will use a pharmacological approach to block excess lactate as a novel target to reduce tau pathology, neuroinflammation, and brain atrophy. Lastly, using a genetic approach, we will explore the impact of microglial derived lactate on brain metabolism, microglia function, tau pathology, neuroinflammation, and brain atrophy.