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Cited by 2Neuroinflammation and Neurodegeneration MechanismsInflammasome and immune disordersNeurological Disease Mechanisms and Treatments

The Double Face of Microglia in the Brain

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Rubio-Osornio, Moisés, Rubio, Carmen, Ganado, Maximiliano, Romo-Parra, Héctor·2026·Neuroglia
DOI 10.3390/neuroglia7010003
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Abstract

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways.

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  • The older binary language of resting versus activated microglia is too limited.

    “This older binary language is now considered too limited.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [9]

    Section 3, “Microglial Activation and Functional Polarization” (page unavailable), says microglial states form a context-dependent continuum that a binary model cannot capture. The paper identifies the older binary framework as M1 versus M2, however, rather than specifically resting versus activated microglia. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In homeostasis, microglia continuously survey the parenchyma, support neuronal integrity, contribute to synaptic remodeling, release trophic factors, and clear debris.

    “Even in homeostasis, microglia continuously survey the parenchyma [6], support neuronal integrity [7], contribute to synaptic remodeling [8], release trophic factors [8], and clear debris [9]”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [9]

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References 129 · Cited by 2

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Authors
Rubio-Osornio, M., Rubio, C., Ganado, M., & Romo-Parra, H.
Affiliations
  • Neurochemistry Department, National Institute of Neurology and Neurosurgery MVS, Mexico City 14269, Mexico
  • Instituto Nacional de Neurología y Neurocirugía (MX)
  • Universidad Autónoma Metropolitana (MX)
  • Neurophysiology Department, National Institute of Neurology and Neurosurgery MVS, Mexico City14269, Mexico
ORCID
Venue
Neuroglia
Publisher
MDPI AG
Published
2026-01-02
Volume
7
Issue
1
Pages
3
ISSN
2571-6980 (ISSN-L)
DOI
10.3390/neuroglia7010003
OpenAlex
W7117961650
Cited by
2
References
129
Citations by year
2026: 2
FWCI
5.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroglia (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, neurodegenerative diseases, neuroinflammation, disease-associated microglia, TREM2, apolipoprotein E, NLRP3 inflammasome, microglial senescence, astrocyte-microglia interaction, metabolic reprogramming, PGC-1α, SIRT1, glycolysis, microglial heterogeneity, synaptic pruning, neuroprotection

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