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Mol. Neurodegener., Mar 27 2025, 20 (1) | https://doi.org/10.1186/s13024-025-00825-0 Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Eun Sun Jung¹, Hayoung Choi¹ and Inhee Mook‑Jung^1,2,3*

¹Convergence Dementia Research Center, Seoul National University College of Medicine, Seoul, South Korea
²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
³Korea Dementia Research Center, Seoul, South Korea

^*Correspondence: Inhee Mook‑Jung

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.

논문정보

형식Review Paper
게재일2025년 03월 (BRIC 등록일 2025-03-30)
연구진국내 연구진
분야 의약학 > 신경의학

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