Lactate as a Regulator of Alzheimer's Pathology

Project Summary/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 presymptomatic 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. Microglia increase glucose uptake in response to amyloid-beta (Aβ) and undergo a metabolic shift from oxidative metabolism to glycolysis with activation. 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 amyloid plaques and blocking lactate metabolism reduces ISF lactate and ISF Aβ. While the role of lactate in the brain and in AD is widely debated, lactate has emerged as an essential metabolite and signaling molecule for neurons and astrocytes. However, little is known about lactate as a regulator of immunometabolism and microglial activity in AD. Our preliminary data shows that genes responsible for lactate production (Ldha) and lactate consumption (Ldhb) are highly expressed in microglia and Ldha expression is elevated in the peri-plaque milieu. Together, this suggests that Aβ aggregation leads to excess lactate production which we hypothesize is due to changes in microglial metabolism and function. While initially protective, we hypothesize that these chronic shifts in microglial metabolism exacerbate Aβ aggregation, neuroinflammation, and functional deficits. 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 Aβ pathology and neuroinflammation. Lastly, using a genetic approach, we will selectively deplete lactate production in microglia to explore the impact of microglial derived lactate on brain metabolism, microglia function, Aβ pathology, and functional deficits.