An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are crucial for microglia and innate immunity in Alzheimer's disease (AD) and neurodegenerative disorders.
• TREM2 undergoes maturation in the secretory pathway and shedding of its ectodomain from the plasma membrane.
• Missense mutations in the immunoglobulin (Ig)-like domain (e.g., p.T66M, p.Y38C) cause TREM2 retention in the endoplasmic reticulum, reducing shedding and phagocytosis.

Purpose of the Study:

• To identify the precise cleavage site of TREM2.
• To investigate the functional consequences of an AD-associated TREM2 variant (p.H157Y) located at the cleavage site.

Main Methods:

• Mass spectrometry was employed to determine the TREM2 cleavage site.
• Analysis of TREM2 shedding and cell surface expression in response to different variants.

Main Results:

• The cleavage site for TREM2 shedding by ADAM proteases was identified C-terminal to histidine 157.
• The p.H157Y variant, associated with AD in the Han Chinese population, enhances TREM2 ectodomain shedding.
• Both reduced shedding (e.g., p.T66M, p.Y38C) and enhanced shedding (p.H157Y) lead to decreased levels of full-length TREM2 on the cell surface.

Conclusions:

• TREM2 shedding is mediated by ADAM proteases at histidine 157.
• Both reduced and enhanced TREM2 ectodomain shedding, driven by different variants, converge to reduce cell surface TREM2 levels.
• This reduction in cell surface TREM2 impairs TREM2-dependent phagocytosis, highlighting a common pathway for neurodegeneration in Alzheimer's disease.