{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:16:41Z","timestamp":1768529801472,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,13]]},"group-title":"Neuroscience","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35NS097283"],"award-info":[{"award-number":["R35NS097283"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01034924"],"award-info":[{"award-number":["R01034924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,13]]},"abstract":"<jats:p>\n                  Adult CNS trauma frequently causes neuronal disconnection and persistent deficits due to failed axon regeneration. While model system screening has identified multiple candidate neural repair pathways, ApoE\u2013LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by\n                  <jats:italic>APOE<\/jats:italic>\n                  variants. ApoE2-expressing mice show reparative corticospinal and raphespinal axon growth with greater motor function than controls after spinal cord injury. Distinct from ApoE in other settings, there is no change in inflammation or scarring. After axotomy, ApoE exerts allele-specific effects on LRP8 localization and signaling in cortical neurons.\n                  <jats:italic>APOE<\/jats:italic>\n                  alleles regulate synaptic organization gene expression by cortical neurons after injury, with little effect on glial gene expression. AAV-mediated overexpression of ApoE2 in mice after spinal trauma increases locomotor recovery and reparative axon growth. Thus, ApoE\u2013LRP8 signaling for axon regrowth following CNS trauma provides a potential therapeutic intervention site.\n                <\/jats:p>","DOI":"10.1101\/2025.10.10.681747","type":"posted-content","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T17:05:24Z","timestamp":1760375124000},"source":"Crossref","is-referenced-by-count":0,"title":["Axon Regeneration and Functional Recovery after Spinal Cord Injury is Enhanced by Allele-Specific ApoE Neuronal Action through LRP8"],"prefix":"10.64898","author":[{"given":"Ramakrishnan","family":"Kannan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingxing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LaShae","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy Z.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa M.","family":"Howard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atrayee","family":"Basu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Ingabire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Sekine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8188-3092","authenticated-orcid":false,"given":"Stephen M.","family":"Strittmatter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025101507500706000_2025.10.10.681747v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01196-1"},{"key":"2025101507500706000_2025.10.10.681747v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0280-3"},{"key":"2025101507500706000_2025.10.10.681747v1.3","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/S1474-4422(23)00287-9","article-title":"Global, regional, and national burden of spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"22","author":"G. B. D. S. C. I. Collaborators","year":"2023","journal-title":"Lancet Neurol"},{"key":"2025101507500706000_2025.10.10.681747v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/S41580-022-00562-Y"},{"key":"2025101507500706000_2025.10.10.681747v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4502"},{"key":"2025101507500706000_2025.10.10.681747v1.6","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/S1474-4422(23)00215-6","article-title":"Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial","volume":"22","year":"2023","journal-title":"Lancet Neurol"},{"key":"2025101507500706000_2025.10.10.681747v1.7","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1097\/WCO.0000000000001205","article-title":"Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial","volume":"36","year":"2023","journal-title":"Curr Opin Neurol"},{"key":"2025101507500706000_2025.10.10.681747v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02940-9"},{"key":"2025101507500706000_2025.10.10.681747v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03306-x"},{"key":"2025101507500706000_2025.10.10.681747v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.058"},{"key":"2025101507500706000_2025.10.10.681747v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108777"},{"key":"2025101507500706000_2025.10.10.681747v1.12","doi-asserted-by":"crossref","first-page":"114070","DOI":"10.1016\/j.expneurol.2022.114070","article-title":"Rabphilin3A reduces integrin-dependent growth cone signaling to restrict axon regeneration after trauma","volume":"353","year":"2022","journal-title":"Exp Neurol"},{"key":"2025101507500706000_2025.10.10.681747v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1161566"},{"key":"2025101507500706000_2025.10.10.681747v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.11.021"},{"key":"2025101507500706000_2025.10.10.681747v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1120684109"},{"key":"2025101507500706000_2025.10.10.681747v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22828-3"},{"key":"2025101507500706000_2025.10.10.681747v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31960-7"},{"key":"2025101507500706000_2025.10.10.681747v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv125"},{"key":"2025101507500706000_2025.10.10.681747v1.19","first-page":"97","article-title":"Genome-wide association study of traumatic brain injury in U","volume":"29","year":"2024","journal-title":"S. military veterans enrolled in the VA million veteran program. Mol Psychiatry"},{"key":"2025101507500706000_2025.10.10.681747v1.20","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-010-0620-2"},{"key":"2025101507500706000_2025.10.10.681747v1.21","doi-asserted-by":"publisher","DOI":"10.1080\/10790268.2008.11760708"},{"key":"2025101507500706000_2025.10.10.681747v1.22","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2018.6052"},{"key":"2025101507500706000_2025.10.10.681747v1.23","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.626192"},{"key":"2025101507500706000_2025.10.10.681747v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4566-05.2006"},{"key":"2025101507500706000_2025.10.10.681747v1.25","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M500114-JLR200"},{"key":"2025101507500706000_2025.10.10.681747v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.03.033"},{"key":"2025101507500706000_2025.10.10.681747v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.06.002"},{"key":"2025101507500706000_2025.10.10.681747v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80860-0"},{"key":"2025101507500706000_2025.10.10.681747v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.12.018"},{"key":"2025101507500706000_2025.10.10.681747v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2620"},{"key":"2025101507500706000_2025.10.10.681747v1.31","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R800077-JLR200"},{"key":"2025101507500706000_2025.10.10.681747v1.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2994-18.2019"},{"key":"2025101507500706000_2025.10.10.681747v1.33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124853"},{"key":"2025101507500706000_2025.10.10.681747v1.34","doi-asserted-by":"crossref","unstructured":"X. Xian , T. Pohlkamp , M. S. Durakoglugil , C. H. Wong , J. K. Beck , C. Lane-Donovan , F. Plattner , J. Herz , Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer\u2019s disease. Elife 7, (2018).","DOI":"10.7554\/eLife.40048"},{"key":"2025101507500706000_2025.10.10.681747v1.35","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1685008"},{"key":"2025101507500706000_2025.10.10.681747v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.014"},{"key":"2025101507500706000_2025.10.10.681747v1.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1131-22.2022"},{"key":"2025101507500706000_2025.10.10.681747v1.38","doi-asserted-by":"crossref","unstructured":"M. I. Elmalky , G. Alvarez-Bolado , A. Younsi , T. Skutella , Axonal Regeneration after Spinal Cord Injury: Molecular Mechanisms, Regulatory Pathways, and Novel Strategies. Biology (Basel) 13, (2024).","DOI":"10.3390\/biology13090703"},{"key":"2025101507500706000_2025.10.10.681747v1.39","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201911505"},{"key":"2025101507500706000_2025.10.10.681747v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0001-8"},{"key":"2025101507500706000_2025.10.10.681747v1.41","first-page":"374","article-title":"Axon regeneration: Splicing up repair mechanisms","volume":"16","year":"2015","journal-title":"Nat Rev Neurosci"},{"key":"2025101507500706000_2025.10.10.681747v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2024.09.009"},{"key":"2025101507500706000_2025.10.10.681747v1.43","doi-asserted-by":"crossref","unstructured":"M. Rozenbaum , M. Rajman , I. Rishal , I. Koppel , S. Koley , K. F. Medzihradszky , J. A. Oses-Prieto , R. Kawaguchi , P. S. Amieux , A. L. Burlingame , G. Coppola , M. Fainzilber , Translatome Regulation in Neuronal Injury and Axon Regrowth. eNeuro 5, (2018).","DOI":"10.1523\/ENEURO.0276-17.2018"},{"key":"2025101507500706000_2025.10.10.681747v1.44","doi-asserted-by":"publisher","DOI":"10.1080\/02699050902926259"},{"key":"2025101507500706000_2025.10.10.681747v1.45","doi-asserted-by":"crossref","unstructured":"L. E. Strattan , D. R. S. Britsch , C. M. Calulot , R. S. J. Maggard , E. L. Abner , L. A. Johnson , W. J. Alilain , Novel Influences of Sex and APOE Genotype on Spinal Plasticity and Recovery of Function after Spinal Cord Injury. eNeuro 8, (2021).","DOI":"10.1523\/ENEURO.0464-20.2021"},{"key":"2025101507500706000_2025.10.10.681747v1.46","doi-asserted-by":"crossref","unstructured":"G. Sienski , P. Narayan , J. M. Bonner , N. Kory , S. Boland , A. A. Arczewska , W. T. Ralvenius , L. Akay , E. Lockshin , L. He , B. Milo , A. Graziosi , V. Baru , C. A. Lewis , M. Kellis , D. M. Sabatini , L. H. Tsai , S. Lindquist , APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Science translational medicine 13, (2021).","DOI":"10.1126\/scitranslmed.aaz4564"},{"key":"2025101507500706000_2025.10.10.681747v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nature24016"},{"key":"2025101507500706000_2025.10.10.681747v1.48","doi-asserted-by":"publisher","DOI":"10.1126\/science.add1236"},{"key":"2025101507500706000_2025.10.10.681747v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07185-7"},{"key":"2025101507500706000_2025.10.10.681747v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28473-8"},{"key":"2025101507500706000_2025.10.10.681747v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2009"},{"key":"2025101507500706000_2025.10.10.681747v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01854-z"},{"key":"2025101507500706000_2025.10.10.681747v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80782-5"},{"key":"2025101507500706000_2025.10.10.681747v1.54","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2006.23.635"},{"key":"2025101507500706000_2025.10.10.681747v1.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1718-15.2015"},{"key":"2025101507500706000_2025.10.10.681747v1.56","doi-asserted-by":"publisher","DOI":"10.1089\/10430349950017563"},{"key":"2025101507500706000_2025.10.10.681747v1.57","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1609896113"},{"key":"2025101507500706000_2025.10.10.681747v1.58","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1934-z"},{"key":"2025101507500706000_2025.10.10.681747v1.59","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.208108"},{"key":"2025101507500706000_2025.10.10.681747v1.60","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abi8593"},{"key":"2025101507500706000_2025.10.10.681747v1.61","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"2025101507500706000_2025.10.10.681747v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3192"},{"key":"2025101507500706000_2025.10.10.681747v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"2025101507500706000_2025.10.10.681747v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0229-21"},{"key":"2025101507500706000_2025.10.10.681747v1.65","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01345-z"},{"key":"2025101507500706000_2025.10.10.681747v1.66","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06812-z"},{"key":"2025101507500706000_2025.10.10.681747v1.67","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"2025101507500706000_2025.10.10.681747v1.68","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp101"},{"key":"2025101507500706000_2025.10.10.681747v1.69","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq562"},{"key":"2025101507500706000_2025.10.10.681747v1.70","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq262"},{"key":"2025101507500706000_2025.10.10.681747v1.71","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074"},{"key":"2025101507500706000_2025.10.10.681747v1.72","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAC1000"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.10.681747","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:47:45Z","timestamp":1768470465000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.10.681747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":72,"URL":"https:\/\/doi.org\/10.1101\/2025.10.10.681747","relation":{},"subject":[],"published":{"date-parts":[[2025,10,13]]},"subtype":"preprint"}}