{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:41:16Z","timestamp":1788972076422,"version":"build-2803163510"},"posted":{"date-parts":[[2025,2,9]]},"group-title":"Neuroscience","reference-count":128,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T00:00:00Z","timestamp":1739059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["80ARC022CA004"],"award-info":[{"award-number":["80ARC022CA004"]}],"id":[{"id":"https:\/\/ror.org\/027ka1x80","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ASAP-024297"],"award-info":[{"award-number":["ASAP-024297"]}],"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS114239"],"award-info":[{"award-number":["R01NS114239"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["UH3NS115064"],"award-info":[{"award-number":["UH3NS115064"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["F31NS13090"],"award-info":[{"award-number":["F31NS13090"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"award":["1U54AG090669-01"],"award-info":[{"award-number":["1U54AG090669-01"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AG04968"],"award-info":[{"award-number":["T32AG04968"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CureAlz Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like\n                  <jats:italic>APOE4,<\/jats:italic>\n                  increase the prevalence and severity of tau, amyloid, and \u03b1-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue (\u201cmiBrain\u201d). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to \u03b1-synuclein pathology. Like the human brain, pathogenic \u03b1-synuclein is increased in\n                  <jats:italic>APOE4\/4<\/jats:italic>\n                  miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in\n                  <jats:italic>APOE4\/4<\/jats:italic>\n                  astrocytes impairs the degradation of soluble \u03b1-synuclein leading to a pathogenic transformation that seeds \u03b1-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in\n                  <jats:italic>APOE4<\/jats:italic>\n                  -mediated pathologies.\n                <\/jats:p>","DOI":"10.1101\/2025.02.09.637107","type":"posted-content","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T04:10:13Z","timestamp":1739160613000},"source":"Crossref","is-referenced-by-count":5,"title":["Cholesterol Dysregulation in APOE4 Astrocytes Promotes \u03b1-Synuclein Pathology in miBrains, a Human Brain Tissue Model"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0937-9331","authenticated-orcid":false,"given":"Louise A.","family":"Mesentier-Louro","sequence":"first","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-7290","authenticated-orcid":false,"given":"Camille","family":"Goldman","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0375-3214","authenticated-orcid":false,"given":"Sebastian","family":"Gaese","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-9360","authenticated-orcid":false,"given":"Alice","family":"Buonfiglioli","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1643-2310","authenticated-orcid":false,"given":"Dimitrios","family":"Kyriakis","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Mount Sinai, New York, NY, USA"},{"name":"Center for Disease Neurogenomics, Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6779-526X","authenticated-orcid":false,"given":"Ashley","family":"Harlock","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-7115","authenticated-orcid":false,"given":"Alain","family":"Ndayisaba","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815"},{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7940-5268","authenticated-orcid":false,"given":"Emily R.","family":"Sartori","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Mount Sinai, New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8604-0014","authenticated-orcid":false,"given":"Abigail","family":"Uchitelev","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Mount Sinai, New York, NY, USA"},{"name":"Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Mount Sinai, New York, NY, USA"},{"name":"Ronald M. 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