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Cited by 68Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPhagocytosis and Immune Regulation

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells

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Akhter, Rumana, Shao, Yvonne, Formica, Shane, Khrestian, Maria, Bekris, Lynn M.·2021·Molecular Immunology
DOI 10.1016/j.molimm.2020.12.035PMC PMC8147571

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Abstract

Alzheimer's disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to Aβ in mouse brain and primary cells. These studies show that microglia are key players in the response to Aβ and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to Aβ, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to Aβ toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. Aβ 42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to Aβ after 24 h requires TREM2 in HMC3 cells. Also, TREM2 inhibits Aβ induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to Aβ toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis and inhibit apoptosis, but may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.

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  • INPP5D regulates microglial functions, including phagocytosis, proliferation, motility, and cytokine release.

    “thereby regulating microglial functions, including phagocytosis, proliferation, motility, and cytokine release.[11][12][13]”

    From <i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease (2023) · cites this paper as [11]

    The Results and Discussion address TREM2’s effects on phagocytosis and inflammatory factors in HMC3 cells, not INPP5D’s regulation of microglial functions. Searches for INPP5D and SHIP1 found no passage addressing the attributed claim; the paper does not establish the claimed effects on proliferation or motility either. Page numbers were not available in our copy. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Akhter, R., Shao, Y., Formica, S., Khrestian, M., & Bekris, L. M.
Affiliations
Cleveland Clinic (US)
Corresponding author
Bekris, Lynn M.
ORCID
Venue
Molecular Immunology
Publisher
Elsevier BV
Published
2021-03
Volume
131
Pages
171-179
ISSN
0161-5890 (ISSN-L)
DOI
10.1016/j.molimm.2020.12.035
PMC
PMC8147571
OpenAlex
W3118400946
Cited by
68
References
19
Citations by year
2026: 10 · 2025: 23 · 2024: 15 · 2023: 6 · 2022: 13 · 2021: 1
FWCI
3.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Immunology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R56 AG063870, R00AG034214)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
TREM2, amyloid-beta 42, Alzheimer's disease, microglia, HMC3 cells, phagocytosis, apoptosis, neuroinflammation, Bcl-2 family proteins, inflammatory cytokines, CXCL10, macrophage inflammatory protein-1alpha, interleukin-8, FGF2, vascular endothelial growth factor, GRO
MeSH terms
THP-1 Cells, Alzheimer Disease, Brain, Cell Line, Humans, Inflammation, Membrane Glycoproteins, Phagocytes, Phagocytosis, Receptors, Immunologic, Amyloid beta-Peptides, Apoptosis, Microglia, U937 Cells, Cell Line, Tumor, Hep G2 Cells, Plaque, Amyloid

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