Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.

INTRODUCTION: Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1  (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear. METHODS: We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake. RESULTS: ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present. DISCUSSION: ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD. HIGHLIGHTS: Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.