{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:02Z","timestamp":1782281042113,"version":"3.54.5"},"posted":{"date-parts":[[2025,1,18]]},"group-title":"Neuroscience","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with the transport and protection of highly vulnerable lipids required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. Human\n                  <jats:italic>APOE<\/jats:italic>\n                  allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimer\u2019s disease (AD); however, the\n                  <jats:italic>specific<\/jats:italic>\n                  molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide bridge-linked dimers and multimers. Here we propose the overarching hypothesis that the super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of\n                  <jats:italic>APOE<\/jats:italic>\n                  alleles on AD risk and amyloid-\u03b2 and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of ApoE homo-dimers\/multimers and heteromeric ApoE complexes such as ApoE-ApoJ and ApoE-ApoD. We thus propose that the inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as the initiating molecular events that ultimately lead to AD in humans.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        <jats:italic>APOE<\/jats:italic>\n                        alleles are the strongest genetic risk factor for sporadic Alzheimer\u2019s disease (AD)\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        <jats:italic>APOE<\/jats:italic>\n                        alleles encode proteins that differ only in the number of Cys\u27f6Arg exchanges\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Despite 30 years of inquiry, mechanisms linking Cys\u27f6Arg exchanges to AD remain unknown<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>PUFA-phospholipids induced disulfide bridge formation in ApoE3 and ApoE2 (but not ApoE4)<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>We hypothesize that disulfide bridges in ApoE protect vulnerable lipids from peroxidation<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        We propose that lipid-protecting disulfide bridges explain\n                        <jats:italic>APOE<\/jats:italic>\n                        allele-dependent AD risks\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.17.633633","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T22:50:15Z","timestamp":1737240615000},"source":"Crossref","is-referenced-by-count":1,"title":["Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer\u2019s disease in humans"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4058-7630","authenticated-orcid":false,"given":"Christopher E.","family":"Ramsden","sequence":"first","affiliation":[{"name":"Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH 251 Bayview Blvd., Baltimore, MD, 21224, USA"},{"name":"Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy G.","family":"Cutler","sequence":"additional","affiliation":[{"name":"Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH 251 Bayview Blvd., Baltimore, MD, 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufeng","family":"Li","sequence":"additional","affiliation":[{"name":"Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH 251 Bayview Blvd., Baltimore, MD, 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Keyes","sequence":"additional","affiliation":[{"name":"Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH 251 Bayview Blvd., Baltimore, MD, 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041021465121000_2025.01.17.633633v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21974"},{"key":"2026041021465121000_2025.01.17.633633v1.2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-3042.2001.00688.x"},{"key":"2026041021465121000_2025.01.17.633633v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.294.5545.1354"},{"key":"2026041021465121000_2025.01.17.633633v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/srep21096"},{"key":"2026041021465121000_2025.01.17.633633v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.5.1977"},{"key":"2026041021465121000_2025.01.17.633633v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"2026041021465121000_2025.01.17.633633v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng0694-180"},{"key":"2026041021465121000_2025.01.17.633633v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0358-2"},{"key":"2026041021465121000_2025.01.17.633633v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14279-8"},{"key":"2026041021465121000_2025.01.17.633633v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24369"},{"key":"2026041021465121000_2025.01.17.633633v1.11","first-page":"1349","article-title":"Effects 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