Axon Regeneration and Functional Recovery from 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 candidate neural repair genes, ApoE – LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by APOE 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_x0002_specific effects on LRP8 localization and signaling in cortical neurons. APOE 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 increased locomotor recovery and reparative axon growth. Thus, a role for ApoE – LRP8 signaling is supported by preclinical and clinical observations, providing a potential site for intervention. Overall design: Age-matched adult (12-13 weeks) female mice of ApoE2 or ApoE4 genotype were subjected to a thoracic dorsal-over hemisection (injured) or shame (control) surgery. All animals received subcutaneous injections of 100 mg/kg ampicillin and 0.1 mg/kg Buprenex twice daily for the first 2 d after surgery and additional injections later as necessary. Eleven days post-surgery, the motor cortices of both SCI-injured and control mice were dissected and processed for single nuclei isolation and RNA sequencing for comparative transcriptomic expression profile analysis.