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Cited by 71Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Targeting Microglia in Alzheimer’s Disease: Pathogenesis and Potential Therapeutic Strategies

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Sun, Zhongqing, Zhang, Xin, So, Kwok-Fai, Jiang, Wen, Chiu, Kin·2024·Biomolecules
DOI 10.3390/biom14070833PMC PMC11274940
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Abstract

Microglia, as resident macrophages in the central nervous system, play a multifunctional role in the pathogenesis of Alzheimer’s disease (AD). Their clustering around amyloid-β (Aβ) deposits is a core pathological feature of AD. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have revealed dynamic changes in microglial phenotypes over time and across different brain regions during aging and AD progression. As AD advances, microglia primarily exhibit impaired phagocytosis of Aβ and tau, along with the release of pro-inflammatory cytokines that damage synapses and neurons. Targeting microglia has emerged as a potential therapeutic approach for AD. Treatment strategies involving microglia can be broadly categorized into two aspects: (1) enhancing microglial function: This involves augmenting their phagocytic ability against Aβ and cellular debris and (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce the neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches for AD treatment have garnered attention. Additionally, natural products show promise in enhancing beneficial effects and suppressing inflammatory responses. Clarifying microglial dynamics, understanding their roles, and exploring novel therapeutic approaches will advance our fight against AD.

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  • Activated microglia secrete proinflammatory cytokines including IL-1β, TNF-α, and IL-6, together with reactive oxygen and nitrogen species, altering neuronal excitability and triggering apoptotic cascades.

    “Activated microglia secrete proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, together with reactive oxygen and nitrogen species, thereby altering neuronal excitability and triggering apoptotic cascades.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [89]

    Section 2 (page not available) says activated microglia secrete TNF-α and IL-1β, and that TNF-α can lead to neuronal apoptosis. It also reports IL-6 release and reactive oxygen and nitrogen species production by a specific microglial subtype, LDAM. The copy does not establish that these products alter neuronal excitability or collectively trigger apoptotic cascades. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Risk variants in glial cell surface genes TREM2, CD33, and ABCA7, enriched in microglia, significantly increase susceptibility to AD.

    “Genetic studies underscore the centrality of glial dysfunction, with risk variants in glial cell surface genes, such as triggering receptor expressed on myeloid cells 2 (TREM2), siglec-3 (CD33), and ATP-binding cassette subfamily A member 7 (ABCA7), which are enriched in microglia, significantly increasing susceptibility to AD [89].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [89]

    Section 3.1 (page unavailable) identifies TREM2 and ABCA7 among AD-susceptibility genes preferentially expressed in microglia, and separately calls CD33 an AD-susceptibility gene widely observed on microglia. It identifies TREM2 as a cell-surface receptor and CD33 as a transmembrane protein, but does not establish that ABCA7 is a cell-surface gene or that variants in each of the three significantly increase susceptibility. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Circulating proinflammatory mediators cross a compromised BBB and trigger microglial activation, fueling neuroinflammation.

    “Moreover, circulating proinflammatory mediators cross a compromised BBB and trigger microglial activation, fueling neuroinflammation [89].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [89]

    Section 3.2, Table 2, mentions blood–brain barrier leakiness, and Section 3.2 links activated microglia to neuroinflammation. Neither passage says that circulating proinflammatory mediators cross a compromised barrier and trigger microglial activation; the section instead describes aggregated Aβ as a trigger. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Mitochondrial dysfunction increases oxidative stress, which acts as a potent trigger for microglial activation.

    “Mitochondrial dysfunction increases oxidative stress, which acts as a potent trigger for microglial activation [89].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [89]

    Section 2, “Microglia in AD Pathogenesis” (page unavailable), describes microglia producing reactive oxygen species and identifies complement signaling and plaques as triggers of microglial activity. Searches for “mitochondrial dysfunction,” “oxidative stress,” and ROS as a trigger found no passage linking mitochondrial dysfunction to oxidative stress that activates microglia. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Sun, Z., Zhang, X., So, K.-F., Jiang, W., & Chiu, K.
Affiliations
  • Xijing Hospital (CN)
  • Jinan University (CN)
  • University of Hong Kong (HK)
Corresponding author
  • Jiang, Wen
  • Chiu, Kin
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2024-07-11
Volume
14
Issue
7
Pages
833
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom14070833
PMC
PMC11274940
OpenAlex
W4400580066
Cited by
71
References
50
Citations by year
2026: 38 · 2025: 32 · 2024: 1
FWCI
3.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
  • Health and Medical Research Fund, Hong Kong, China (14151281, MRP-092-17X, LHJJ24JC13)
  • Midstream Research Program for Universities, Hong Kong, China (14151281, MRP-092-17X, LHJJ24JC13)
  • Xijing Innovation Research Institute Joint Innovation Fund, Xian, China (14151281, MRP-092-17X, LHJJ24JC13)
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
microglia, Alzheimer's disease, amyloid-beta, tau protein, microglial phagocytosis, neuroinflammation, microglial phenotype, TNF signaling, microglia-targeted therapy, natural products, synapse damage, aging
MeSH terms
Alzheimer Disease, Animals, Humans, Phagocytosis, Amyloid beta-Peptides, Microglia

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