SHIP inhibition mediates select TREM2-induced microglial functions

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.