biostudies-literatureUnknownKannan RNINDS NIH HHSAdult 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-LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by <i>APOE</i> 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. <i>APOE</i> alleles regulate synaptic organization gene expression by cortical neurons after ibioRxiv : the preprint server for biology2025.10.10.681747https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632883biostudies-literatureAxon Regeneration and Functional Recovery after Spinal Cord Injury is Enhanced by Allele-Specific ApoE Neuronal Action through LRP8.PMC12632883R35 NS097283Kannan RLin NZHoward EMIngabire INicholson LSekine YWang XBasu AStrittmatter SMfalseAxon Regeneration and Functional Recovery after Spinal Cord Injury is Enhanced by Allele-Specific ApoE Neuronal Action through LRP8.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-LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by <i>APOE</i> 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. <i>APOE</i> alleles regulate synaptic organization gene expression by cortical neurons after i2025-01-01T00:00:00Z2025 Oct2026-06-01T03:18:14.075Z2026-06-01T03:10:50.655ZS-EPMC126328834127883210.1101/2025.10.10.681747