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Numerous in\u00a0vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of A\u03b2 aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of A\u03b2 aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that A\u03b242 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of A\u03b242 demonstrate such ability. Extracted cholesterol\u00a0interacts with A\u03b242 and accelerates its on\u2010membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates A\u03b242 aggregation. The discovered ability of A\u03b242 to remove cholesterol from membranes resulted in three major AD\u2010related events. First, free cholesterol catalyzes the assembly of A\u03b242 in aggregates, which is the mechanism by which physiologically important A\u03b242 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane\u2010bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70380-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70380","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T11:57:52Z","timestamp":1770724672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amyloid \u03b2\u2014Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology"],"prefix":"10.1111","volume":"170","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-1873","authenticated-orcid":false,"given":"Rishiram","family":"Baral","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1571-1978","authenticated-orcid":false,"given":"Ruan","family":"van Deventer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-8302","authenticated-orcid":false,"given":"Yuri L.","family":"Lyubchenko","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474\u20109726.2011.00685.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472\u20106807\u20106"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45592"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00688"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2021.02.010"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.12.007"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.09.022"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.14"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.762526"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4183"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1430465"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2017.03.009"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806077200"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021\u20109797(75)90018\u20101"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3012"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/814390"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010015\u20101449\u20105"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.690372"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14693"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904532106"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55519-7"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2006.02.006"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032944"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/814390"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","unstructured":"Grobelny J. 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