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Cited by 18Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

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Li, Ke, Ran, Beibei, Wang, Yu, Liu, Lulu, Li, Weidong·2022·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2022.999061PMC PMC9485805
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Abstract

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease mainly characterized by memory loss and cognitive decline. The etiology of AD is complex and remains incompletely understood. In recent years, genome-wide association studies (GWAS) have increasingly highlighted the central role of microglia in AD pathology. As a trans-membrane receptor specifically present on the microglia in the central nervous system, phosphatidylinositol-specific phospholipase C gamma 2 (PLCγ2) plays an important role in neuroinflammation. GWAS data and corresponding pathological research have explored the effects of PLCG2 variants on amyloid burden and tau pathologies that underline AD. The link between PLCγ2 and other AD-related effectors in human and mouse microglia has also been established, placing PLCγ2 downstream of the triggering receptor expressed on myeloid cells 2 (TREM2), toll-like receptor 4 (TLR4), Bruton’s tyrosine kinase (BTK), and colony-stimulating factor 1 receptor (CSF1R). Because the research on PLCγ2’s role in AD is still in its early stages, few articles have been published, therefore in this paper, we integrate the relevant research published to date, review the structural features, expression patterns, and related pathways of PLCγ2, and summarize the recent studies on important PLCG2 variants related to AD. Furthermore, the possibility and challenge of using PLCγ2 to develop therapeutic drugs for AD are also discussed.

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  • The loss-of-function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.

    “Conversely, the loss‐of‐function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [28]

    The section on the M28L variant (page unavailable) reports increased late-onset Alzheimer’s disease risk and resistance to a BTK inhibitor; the paper’s references identify ibrutinib as a BTK inhibitor. It does not establish that M28L is loss-of-function, and it explicitly says that M28L’s interaction with Aβ and other AD pathological markers had not been studied. The claim that it worsens Aβ pathology is therefore unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Li, K., Ran, B., Wang, Y., Liu, L., & Li, W.
Affiliations
Beijing University of Chinese Medicine (CN)
Corresponding author
Li, Weidong
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2022-09-06
Volume
10
Pages
999061-999061
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2022.999061
PMC
PMC9485805
OpenAlex
W4294724546
Cited by
18
References
143
Citations by year
2026: 5 · 2025: 8 · 2024: 4 · 2023: 1
FWCI
0.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
PLCγ2, Alzheimer's disease, microglia, neuroinflammation, TREM2, TLR4, Bruton's tyrosine kinase, CSF1R, amyloid burden, tau pathology, therapeutic target

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