Increased CD33 levels tune activation and function of induced human microglial cells through inhibition of the TREM2 pathway

Summary The microglial CD33 gene is overexpressed in the brains of individuals with Alzheimer’s disease, and multiple CD33 genetic variants are directly linked to disease risk. Here, we investigate CD33 function in induced human microglial cells by increasing or decreasing CD33 levels with AAV6-mediated gene transfer and with CD33-targeting siRNA, respectively. Phagocytosis of oligomeric amyloid beta into live microglia was doubled by reducing CD33 levels, with concomitant increases in secreted TREM2 and in TREM2 activation as assayed by phosphorylation of downstream SYK. Increasing CD33 had opposing effects on microglial activity, decreasing amyloid beta uptake by approximately half, reducing LPS-induced increases in IL-10, and decreasing the efficacy of a TREM2-activating antibody. Experiments combining siRNA and AAV6 demonstrated a linear relationship between CD33 protein and amyloid beta uptake. Results show that CD33 largely governs multiple microglial functions associated with Alzheimer’s disease and affects both pharmacological and physiological activation of TREM2.