Title : Microglial energy metabolism disorder in Alzheimer’s disease
Neuroinflammation is a hallmark of Alzheimer’s disease (AD). Microglia are the resident immune cells in the central nerves system (CNS) and function in many aspects of neuroinflammation. The immune functions of microglia such as surveillance and clearance are gradually lost along with aging and the progression of AD. However, what drives such microglial dysfunction is poorly understood. Here, we show how a positive feedback loop in microglia—comprising metabolic, histone lactylation, and transcriptional layers—drives microglial dysfunction and AD pathogenesis, and we demonstrate that inhibiting this vicious cycle in microglia can ameliorate neuroinflammation, Aβ burden and cognitive deficits in AD model mice. Specifically, we found that glycolytic pathway is abnormal activation in Aβ-associated microglia, which resulted in lactate accumulation and elevated histone lactylation (specifically detecting elevated H4K12la marks in microglia). We subsequently found that this lactate-dependent histone modification is enriched at the promoters of glycolytic genes (e.g., Pkm). We confirmed that this enrichment activates transcription and thereby increases glycolysis activity, and ultimately demonstrate that a glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Microglia-specific ablation or pharmacologic inhibition of PKM2 attenuated microglial activation, ameliorated neuroinflammation, and improved spatial learning and memory in AD mice. Thus, beyond demonstrating a role for histone lactylation in a neurodegenerative disease and showing how multi-layered regulatory impacts attend altered glucose metabolism in microglia, our study illustrates that disrupting a positive feedback loop may support the development of innovative AD therapies.
What will audience learn from your presentation?
- Metabolism disorder is an early causal factor that drives microglial disfunction and neuroinflammation.
- Metabolic-epigenetic crosstalk regulates microglial metabolism disorder in AD.
- AD pathogenesis could be attributed to a system of positive feedback loops, rather than a liner cascade, and targeting the positive feedback loops may support the development of innovative AD therapies.