Inhibition of Acyl-CoA: Cholesterol Acyltransferase 1 Promotes Shedding of Soluble TREM2 and LRP1-Dependent Phagocytosis of Amyloid β Protein in Microglia
Hovde, M. J.; Maaser-Hecker, A.; Tanzi, R. E.
Show abstract
Lipid regulation plays a major role in the pathogenesis of Alzheimers 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 {beta}-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 {beta} (A{beta}). 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 A{beta} in a sTREM2- and LRP1-dependent manner suggesting new avenues for treating and preventing AD.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia 94%
- Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's Disease 93%
- Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone 93%
Similar papers in this journal
- The Cholesteryl Ester Transfer Protein (CETP) raises Cholesterol Levels in the Brain and affects Presenilin-mediated Gene Regulation. 93%
- Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol 93%
- Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux 91%
Similar papers in this journal
- Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases 93%
- Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures 93%
- SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration 92%
Similar papers in this journal
- Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's Disease 94%
- Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models 93%
- Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.