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SHIP inhibition mediates select TREM2-induced microglial functions.

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Molecular Immunology
|April 13, 2024
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Summary

Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is crucial for microglial neuroprotection in Alzheimer's Disease (AD). This study shows SH2-containing inositol-5'-phosphatase 1 (SHIP1) negatively regulates TREM2 functions, offering therapeutic insights.

Keywords:
Alzheimer’s diseaseMicrogliaPhagocytosisSHIP inhibitorsSHIP1TREM2

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Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia are key players in Alzheimer's Disease (AD) pathology.
  • Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is vital for microglial neuroprotective functions.
  • The TREM2 R47H variant is a significant genetic risk factor for AD, associated with loss-of-function.

Purpose of the Study:

  • To investigate the role of TREM2 in human microglia-like HMC3 cells.
  • To explore the regulatory function of SH2-containing inositol-5 omino-phosphatase 1 (SHIP1) on TREM2-mediated microglial functions.
  • To assess the impact of TREM2 variants and SHIP1 modulation on microglial phagocytosis, lysosomal capacity, and mitochondrial activity.

Main Methods:

  • Utilized stable human microglia-like HMC3 cell lines expressing wild-type TREM2, R47H variant, or deficient in TREM2.
  • Assessed phagocytosis of amyloid-beta (Aβ) and apoptotic neurons.
  • Measured lysosomal capacity and mitochondrial activity.
  • Investigated the effects of SHIP1 introduction and pharmacological inhibition of SHIP1/SHIP2.

Main Results:

  • Functional TREM2 is essential for Aβ phagocytosis, lysosomal capacity, and mitochondrial activity.
  • The TREM2 R47H variant showed enhanced phagocytosis of apoptotic neurons.
  • SHIP1 acts as a negative regulator of TREM2-mediated functions.
  • Inhibition of SHIP1 and SHIP2 enhanced Aβ phagocytosis and lysosomal capacity.
  • SHIP1/2 inhibition improved mitochondrial function in TREM2-deficient cells.

Conclusions:

  • TREM2 plays a critical role in essential microglial functions relevant to AD.
  • SHIP1 negatively regulates TREM2-dependent microglial activities.
  • Targeting TREM2 and SHIP1 pathways presents a potential therapeutic strategy for neurodegenerative diseases like AD.