Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases

Abstract

Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining brain homeostasis. However, in neurodegenerative conditions, microglial cells undergo metabolic reprogramming in response to pathological stimuli, including Aβ plaques, Tau tangles, and α-synuclein aggregates. This metabolic shift is characterized by a transition from oxidative phosphorylation (OXPHOS) to glycolysis, increased glucose uptake, enhanced production of lactate, lipids, and succinate, and upregulation of glycolytic enzymes. These metabolic adaptations result in altered microglial functions, such as amplified inflammatory responses and diminished phagocytic capacity, which exacerbate neurodegeneration. This review highlights recent advances in understanding the molecular mechanisms underlying microglial metabolic reprogramming in neurodegenerative diseases and discusses potential therapeutic strategies targeting microglial metabolism to mitigate neuroinflammation and promote brain health. Microglial Metabolic Reprogramming in Neurodegenerative Diseases This graphical abstract illustrates the metabolic shift in microglial cells in response to pathological stimuli and highlights potential therapeutic strategies targeting microglial metabolism for improved brain health.

Keywords: Alzheimer's disease; Metabolic reprogramming; Microglia; Multiple sclerosis; Parkinson's disease.

Fig. 1

Microglia metabolic reprogramming during inflammation This infographic illustrates the metabolic reprogramming of microglial cells under normal and inflammatory conditions. In a healthy state, microglial cells primarily rely on oxidative phosphorylation (OXPHOS) for energy production. However, during inflammation, microglia shift their metabolic preference towards glycolysis. This metabolic reprogramming is characterized by increased glucose uptake, lactate production, lipid synthesis, and accumulation of succinate, along with an upregulation of glycolytic enzymes. As a consequence, microglial inflammatory responses are amplified, while phagocytic function is diminished

Fig. 2

Schematic representation of fatty acid metabolism pathways and their influence on microglial activation and phenotypes Fatty Acid Oxidation: Fatty acids are converted to fatty acyl-CoA by acyl-CoA synthetases (ACSs). Fatty acyl-CoA molecules are transported into the mitochondria by carnitine palmitoyltransferase 1 (CPT1) for fatty acid oxidation, generating ATP.Fatty Acid Synthesis: Fatty acids are synthesized in the cytoplasm, with saturated fatty acids (SFAs) produced via fatty acid synthase (FAS) and unsaturated fatty acids (UFAs) generated through the action of stearoyl-CoA desaturase (SCD).Fatty acids modulate microglial activation and phenotypes. Short-chain fatty acids (SCFAs) regulate resting microglia through free fatty acid receptor 2 (FFAR2). Unsaturated fatty acids (UFAs) and omega-3 polyunsaturated fatty acids (omega-3 PUFAs) modulate anti-inflammatory microglia via PPAR-γ signaling. Omega-6 polyunsaturated fatty acids (omega-6 PUFAs), like arachidonic acid, are upregulated during pro-inflammatory activation via TLR4 signaling. Saturated fatty acids (SFAs) also activate pro-inflammatory microglia through TLR4 signaling

Fig. 3

Metabolic Reprogramming of Microglia inAD In AD, microglia are exposed to various stimuli, including Aβplaques, Tau tangles, and cellular debris. As a result, microglial cells undergo metabolic reprogramming to adapt to these challenging conditions.The metabolic shift in AD microglia involves changes in energy production pathways, such as a transition from OXPHOS to glycolysis, enhanced PPP and mitochondrial respiratory capacity. These metabolic adaptations in microglia lead to altered cellular functions, including amplified inflammatory responses and diminished phagocytic capacity