Laboratory for Translational Research in Neuropsychiatric Disorders (TREND), BRAINCITY: Center of Excellence for Neural Plasticity and Brain Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland.
Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
Transl Neurodegener. 2023 Oct 31;12(1):48. doi: 10.1186/s40035-023-00382-w.
Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer's disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.
小胶质细胞是大脑中的固有免疫细胞，它们在调节大脑健康和疾病方面的作用越来越受到关注。小胶质细胞在中枢神经系统中发挥多种功能，包括监视、吞噬和释放各种可溶性因子。重要的是，它们的大多数功能都与代谢变化密切相关。这种核心小胶质细胞特性和代谢之间的自然相互依存关系为通过营养或代谢干预来调节小胶质细胞活性提供了独特的机会。在这篇综述中，我们检查了现有的科学文献，以综合假说，即阿尔茨海默病（AD）中小胶质细胞对淀粉样β（Aβ）聚集体的吞噬作用可以通过代谢干预来选择性增强。我们首先回顾了小胶质细胞代谢的基础知识，以及常见代谢物（如葡萄糖、脂质、酮体、谷氨酰胺、丙酮酸和乳酸）对小胶质细胞炎症和吞噬特性的影响。接下来，我们检查了 AD 中小胶质细胞代谢失调的证据。随后，我们回顾了代谢操纵小胶质细胞功能的体内研究，以确定它们在 AD 中的治疗潜力。最后，我们讨论了代谢因素对小胶质细胞吞噬健康突触的影响，这也是 AD 进展的一个病理过程。最后，我们列出了在采用利用小胶质细胞吞噬作用清除 AD 和其他神经退行性疾病中病理性蛋白沉积的策略之前需要解决的当前挑战。
