Abstract
IntroductionAxonal injury results in long‐term neurological deficits in traumatic brain injury (TBI) patients. Apolipoprotein E (ApoE) has been reported to activate intracellular adaptor protein Disabled‐1 (Dab1) phosphorylation via its interaction with ApoE receptors. The Dab1 pathway acts as a regulator of axonal outgrowth and growth cone formation in the brain.AimsWe hypothesized that ApoE may alleviate axonal injury and regulate axonal regeneration via the Dab1 pathway after TBI.ResultsIn this study, we established a model of controlled cortical impact (CCI) to mimic TBI in vivo. Using diffusion tensor imaging to detect white matter integrity, we demonstrated that APOE‐deficient mice exhibited lower fractional anisotropy (FA) values than APOE+/+ mice at 28 days after injury. The expression levels of axonal regeneration and synapse plasticity biomarkers, including growth‐associated protein 43 (GAP43), postsynaptic density protein 95 (PSD‐95), and synaptophysin, were also lower in APOE‐deficient mice. In contrast, APOE deficiency exerted no effects on the levels of myelin basic protein (MBP) expression, oligodendrocyte number, or oligodendrocyte precursor cell number. Neurological severity score (NSS) and behavioral measurements in the rotarod, Morris water maze, and Y maze tests revealed that APOE deficiency caused worse neurological deficits in CCI mice. Furthermore, Dab1 activation downregulation by the ApoE receptor inhibitor receptor‐associated protein (RAP) or Dab1 shRNA lentivirus attenuated the beneficial effects of ApoE on FA values, GAP43, PSD‐95, and synaptophysin expression, and neurological function tests. Additionally, the effects of ApoE on axonal regeneration were further validated in vitro. In a mechanical scratch injury model of primary cultured neurons, recombinant ApoE protein treatment enhanced axonal outgrowth and growth cone formation in injured neurons; however, these effects were attenuated by Dab1 shRNA, consistent with the in vivo results.ConclusionCollectively, these data suggest that ApoE promotes axonal regeneration partially through the Dab1 pathway, thereby contributing to functional recovery following TBI.
Highlights
Axonal injury results in long-term neurological deficits in traumatic brain injury (TBI) patients
Collectively, these data suggest that Apolipoprotein E (ApoE) promotes axonal regeneration partially through the Dab[1] pathway, thereby contributing to functional recovery following TBI
We found that there was no difference in the fractional anisotropy (FA) value between the injury groups at 3 days postinjury, indicating that ApoE may exert no effects on acute axonal injury, which is supported by amyloid precursor protein (APP) staining in white matter
Summary
Axonal injury results in long-term neurological deficits in traumatic brain injury (TBI) patients. The Dab[1] pathway acts as a regulator of axonal outgrowth and growth cone formation in the brain. Aims: We hypothesized that ApoE may alleviate axonal injury and regulate axonal regeneration via the Dab[1] pathway after TBI. The expression levels of axonal regeneration and synapse plasticity biomarkers, including growth-associated protein 43 (GAP43), postsynaptic density protein 95 (PSD-95), and synaptophysin, were lower in APOE-deficient mice. Dab[1] activation downregulation by the ApoE receptor inhibitor receptor-associated protein (RAP) or Dab[1] shRNA lentivirus attenuated the beneficial effects of ApoE on FA values, GAP43, PSD-95, and synaptophysin expression, and neurological function tests. In a mechanical scratch injury model of primary cultured neurons, recombinant ApoE protein treatment enhanced axonal outgrowth and growth cone formation in injured neurons; these effects were attenuated by Dab[1] shRNA, consistent with the in vivo results. Strategies to promote axonal regeneration may provide promising benefits for TBI therapies
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