TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant

Area of Science:

• Neuroscience
• Immunology
• Biochemistry

Background:

• Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a crucial role in innate immunity and is implicated in neurological diseases.
• Understanding the regulation of TREM2 shedding is vital for developing therapeutic strategies.

Purpose of the Study:

• To characterize the proteolytic cleavage events responsible for TREM2 shedding.
• To identify the specific proteases involved in TREM2 shedding.
• To investigate the shedding of Alzheimer's disease-associated TREM2 variants.

Main Methods:

• Primary cultures of human macrophages, murine microglia, and TREM2-expressing HEK293 cells were used.
• Protease inhibitors, siRNA targeting ADAM10 and ADAM17, and mass spectrometry were employed.
• Analysis of TREM2 shedding in response to genetic variants and pharmacological inhibitors.

Main Results:

• TREM2 shedding is a constitutive process mediated primarily by ADAM10, releasing a 17 kDa N-terminal fragment.
• Cleavage occurs predominantly at the H157-S158 peptide bond.
• The Alzheimer's disease-associated H157Y TREM2 variant exhibited accelerated shedding, potentially via an ADAM10-independent mechanism.

Conclusions:

• ADAM10 is a key sheddase for TREM2, offering a potential therapeutic target.
• The accelerated shedding of the H157Y TREM2 variant may contribute to Alzheimer's disease pathogenesis.
• These findings provide insights into modulating innate immune responses in neurological disorders.