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Cited by 124Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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

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Jung, Eun Sun, Choi, Hayoung, Mook-Jung, Inhee·2025·Molecular Neurodegeneration
DOI 10.1186/s13024-025-00825-0PMC PMC11948825
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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.

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  • Increases in 3- and 4-hydroxyphenylacetic acid in 4s2M are consistent with alterations in aromatic amino acid-related metabolic flux; such metabolites can arise from tyrosine and monoamine pathways and may reflect systemic metabolic influences rather than direct energetic pathway remodeling.

    “In contrast, increases in 3- and 4-hydroxyphenylacetic acid in 4s2M are consistent with alterations in aromatic amino acid–related metabolic flux; such metabolites can arise from tyrosine and monoamine pathways and may reflect systemic metabolic influences rather than direct energetic pathway remodeling”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Jung et al., 2025

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Authors
Jung, E. S., Choi, H., & Mook-Jung, I.
Affiliations
Seoul National University (KR)
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2025-03-27
Volume
20
Issue
1
Pages
37-37
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-025-00825-0
PMC
PMC11948825
OpenAlex
W4408893878
Cited by
124
References
74
Citations by year
2026: 88 · 2025: 36
FWCI
11.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Dementia Research Center (RS-2020-KH106747, RS-2020-KH106773)
  • National Research Foundation of Korea (RS-2023-00274420)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, neuroinflammation, metabolic reprogramming, TREM2, apolipoprotein E, HIF-1α, oxidative phosphorylation, glycolysis, hexokinase 2, AMPK, lipid metabolism, cholesterol transport, amyloid-beta clearance, lipoprotein lipase, ABCA7, PPARγ, amino acid metabolism, kynurenine pathway, indoleamine 2,3-dioxygenase, pentose phosphate pathway, glucose-6-phosphate dehydrogenase, APOE ε4, NR1D1, Syk, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Humans, Microglia, Lipid Metabolism

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