Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Abstract

Alzheimer's disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation and glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts as an energy sensor, coordinating lipid and glucose metabolism. TREM2 and APOE regulate microglial lipid homeostasis, influencing Aβ clearance and immune responses. LPL and ABCA7, both associated with AD risk, modulate lipid processing and cholesterol transport, linking lipid metabolism to neurodegeneration. PPARG further supports lipid metabolism by regulating microglial inflammatory responses. Amino acid metabolism also contributes to microglial function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked to AD pathology. Additionally, glucose-6-phosphate dehydrogenase regulates the pentose phosphate pathway, maintaining redox balance and immune activation. Dysregulated glucose and lipid metabolism, influenced by genetic variants such as APOE4, impair microglial responses and exacerbate AD progression. Recent findings highlight the interplay between metabolic regulators like REV-ERBα, which modulates lipid metabolism and inflammation, and Syk, which influences immune responses and Aβ clearance. These insights offer promising therapeutic targets, including strategies aimed at HIF-1α modulation, which could restore microglial function depending on disease stage. By integrating metabolic, immune, and genetic factors, this review underscores the importance of microglial immunometabolism in AD. Targeting key metabolic pathways could provide novel therapeutic strategies for mitigating neuroinflammation and restoring microglial function, ultimately paving the way for innovative treatments in neurodegenerative diseases.

Keywords: APOE; Aβ; HIF; Hexokinase; Immunometabolism; Metabolic reprogramming; Microglia; Neuroinflammation; TREM2; Tau.

Fig. 1

Major metabolic alterations and regulatory factors in AD microglia revealed by immuno-metabolomics approaches. Microglia function and phenotype change dynamically as AD pathogenesis progresses, accompanied by significant metabolic alterations. Initially, these cells demonstrate metabolic flexibility, but as the disease becomes chronic, microglia gradually lose their adaptive capacity. This reliance on biased and fragmented metabolic pathways eventually leads to insufficient energy and material supply, resulting in functional impairment and accelerated disease progression. The first notable metabolic shift in AD microglia involves glucose metabolism, characterized by excessive glucose uptake and increased dependence on non-aerobic glycolysis via HIF-1α pathway. This change subsequently leads to the inhibition and breakdown of mitochondrial energy metabolism. Furthermore, prolonged exposure to Aβ plaques, neurofibrillary tangles (NFTs), and excessive cell debris dramatically alters overall lipid metabolism, resulting in the accumulation of lipid droplets (LDs). Microglia with excessive LD accumulation, known as lipid-droplet-accumulating microglia (LDAMs), exhibit significantly reduced phagocytic ability and enhanced inflammatory properties. Recent studies have highlighted the crucial roles of APOE and TREM2, both high-risk genes for AD, in mediating these metabolic transitions in microglia. These genes are increasingly recognized as key players in modulating microglial function and metabolism in the context of AD. The advent of multi-omics approaches has accelerated the identification of candidate substances involved in microglial function and metabolic regulation pathways. This comprehensive analysis provides a deeper understanding of the complex interplay between immune response and metabolism in AD microglia

Fig. 2

An overview of major metabolic pathways. Cellular metabolism is a complex network of interconnected pathways that respond to internal and external signals to meet the cell's needs. These pathways function in a coordinated manner to produce essential components for cellular function and are subject to regulation by various signaling mechanisms. Here is an overview of the major metabolic pathways and their roles. Glycolysis is the process by which glucose is converted into pyruvate. Subsequently, pyruvate can further transform into lactate or be integrated into the tricarboxylic acid (TCA) cycle. Within the TCA cycle, pyruvate undergoes a series of reactions that produce NADH and FADH2, which the oxidative phosphorylation (OXPHOS) electron transport chain (ETC) system uses to generate ATP. Furthermore, glycolysis supplies intermediates for the pentose phosphate pathway (PPP), which produces ribose for nucleotides and amino acids. Lipid metabolism involves synthesizing fatty acids and lipid transportation, a process involving citrate derived from the TCA cycle. Moreover, it has been demonstrated that fatty acids can undergo oxidation, generating NADH and FADH2, which, in turn, promote ATP production through the OXPHOS. Amino acid metabolism also provides vital nutrients for the TCA cycle and plays a significant role in protein biosynthesis and adequate cellular activation. The intricate interconnection and regulation of these pathways by cellular signaling ensure metabolic activity aligns with the cell's requirements. This coordinated system enables cells to produce energy and essential molecules for various physiological processes efficiently