Inhibition of Acyl-CoA: Cholesterol Acyltransferase 1 Promotes Shedding of Soluble TREM2 and LRP1-Dependent Phagocytosis of Amyloid β Protein in Microglia

Lipid regulation plays a major role in the pathogenesis of Alzheimer’s disease (AD). In AD patients and transgenic mice, microglia exhibit increased expression of SOAT1 , encoding Acyl-CoA: Cholesterol Acyltransferase 1 (ACAT1), which catalyzes the production of cholesteryl esters in lipid droplets. ACAT1 Inhibition has been reported to reduce β-amyloid pathology. However, the molecular mechanism underlying this effect remains unknown. Here, we show ACAT1 inhibition in mouse and human iPSC- derived microglia upregulates LRP1 levels and shedding of soluble TREM2 (sTREM2) owing to enhanced cleavage of TREM2 by ADAM10/17. Knocking out TREM2 or preventing sTREM2 release abrogated the ability of ACAT1 inhibition to enhance microglial uptake of amyloid β (Aβ). This could be rescued by the addition of recombinant sTREM2, but only in the presence of LRP1. Collectively, these data indicate ACAT1 inhibition increases microglial uptake of Aβ in a sTREM2- and LRP1-dependent manner suggesting new avenues for treating and preventing AD.