Human Apolipoprotein E Isoforms Influence Neurite Outgrowth and Regeneration In Vitro and In Vivo

Abstract

Translating spinal cord injury (SCI) therapies which promote axonal regeneration from preclinical animal models into the human population is challenging. One potential obstacle is that human genetic predispositions may limit the efficacy of such experimental treatments. The clinically relevant ApoE4 (E4) allele, present in about 14% of the human population, corresponds to an increased incidence of Alzheimer's disease—however, its role in recovery from SCI is poorly understood despite suggestive data implicating its involvement. Indeed, two clinical studies found that SCI individuals with the E4 allele had less motor recovery than individuals without the allele despite longer time in rehabilitation. ApoE4 may mediate this diminished recovery by limiting regeneration and sprouting. Robust regeneration is energy intensive and requires efficient mitochondria, and studies have shown that ApoE4 impairs mitochondrial function. Given these mitochondrial deficits, we hypothesize that ApoE4 can impair regeneration and sprouting. To test this hypothesis, we investigated the impact of ApoE4 on sprouting and neurite outgrowth. In our experiments, we cultured dorsal root ganglia neurons from mice expressing human ApoE isoforms—ApoE2 (E2), ApoE3 (E3), or ApoE4—under the control of the endogenous mouse ApoE promoter. We then analyzed differences in 1) neurite complexity and 2) robustness of outgrowth between genotypes. In two of three independent experiments, E4 neurons had decreased neurite outgrowth and decreased neurite branching compared to E2 and E3 neurons. Data from the Spot Assay, an in vitro model of the glial scar and CNS regeneration, also suggest that chondroitin sulfate proteoglycans may inhibit regeneration in E4 neurons to an even greater extent than in E3 neurons. In addition, with preliminary in vivo data, we are beginning to characterize serotonergic sprouting after lateral C2 hemisection in mice of each ApoE genotype. Since outgrowth, sprouting, and regeneration all partially mediate recovery after CNS injury, impairments in these processes can adversely affect recovery. These foundational studies address not only the possible genetic influence of ApoE4 on recovery from CNS injury, but also a critical gap in knowledge—whether there is a genetic contribution underlying responses to treatment in SCI individuals.Support or Funding InformationUniversity of Kentucky Startup FundsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.