{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:29:33Z","timestamp":1783524573110,"version":"3.55.0"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","award":["T32 AG000222\u201031"],"award-info":[{"award-number":["T32 AG000222\u201031"]}],"id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG000222"],"award-info":[{"award-number":["T32AG000222"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O\u2010acyltransferase 1\/Acyl\u2010coenzymeA: Choleseterol Acyltransferase 1\u00a0(SOAT1) expression, encoding Acyl\u2010coenzymeA: Cholesterol Acyltransferase 1 \u00a0(ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (A\u03b2) pathology, though the mechanism is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We inhibited ACAT1 using avasimibe (AV) in wild\u2010type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low\u2010density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell\u2010derived microglia and measured the impact on A\u03b2 uptake to determine the mechanism through which the inhibition of ACAT1 enhances A\u03b2 uptake.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>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\u2010enhanced A\u03b2 uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>ACAT1 inhibition promotes microglial A\u03b2 uptake in a sTREM2\u2010 and LRP1\u2010dependent manner, offering insights into novel therapeutic strategies for AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia\u2010mediated A\u03b2 uptake.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Increased A\u03b2 uptake is dependent on the presence of both TREM2 and LRP1.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10\/17 to release sTREM2.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Treatment of microglial cells with sTREM2 rescues A\u03b2 uptake in TREM2 KO BV2 cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Inhibition of ACAT1 promotes A\u03b2 uptake through increased shedding of TREM2, which enhances A\u03b2 uptake through a LRP1\u2010dependent mechanism.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70879","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T11:40:12Z","timestamp":1762861212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of Acyl\u2010CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low\u2010density lipoprotein receptor 1 (LRP1)\u2010dependent phagocytosis of amyloid beta protein in microglia"],"prefix":"10.1002","volume":"21","author":[{"given":"Moriah J.","family":"Hovde","sequence":"first","affiliation":[{"name":"Department of Neurology Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital and Harvard Medical School  Charlestown Massachusetts 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