Apolipoprotein E promotes white matter remodeling via the Dab1‐dependent pathway after traumatic brain injury
Autor: | Jianhua Peng, Zhijian Huang, Cheng Yin, Yue Wu, Jianjun Zhong, Li Jiang, Chongjie Cheng, Xiaochuan Sun, Yong Jiang, Fang Cao, Zongduo Guo |
---|---|
Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Apolipoprotein E medicine.medical_specialty Traumatic brain injury Morris water navigation task Nerve Tissue Proteins Mice 03 medical and health sciences Apolipoproteins E 0302 clinical medicine Disabled‐1 Physiology (medical) Internal medicine Brain Injuries Traumatic medicine Animals Pharmacology (medical) Gap-43 protein Cells Cultured apolipoprotein E Mice Knockout Pharmacology biology business.industry traumatic brain injury axonal regeneration Original Articles medicine.disease DAB1 White Matter Oligodendrocyte Myelin basic protein Mice Inbred C57BL Psychiatry and Mental health Diffusion Tensor Imaging 030104 developmental biology medicine.anatomical_structure Endocrinology nervous system biology.protein Synaptophysin Original Article business 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | CNS Neuroscience & Therapeutics |
ISSN: | 1755-5949 1755-5930 |
Popis: | Introduction Axonal 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. Aims We hypothesized that ApoE may alleviate axonal injury and regulate axonal regeneration via the Dab1 pathway after TBI. Results In 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. Conclusion Collectively, these data suggest that ApoE promotes axonal regeneration partially through the Dab1 pathway, thereby contributing to functional recovery following TBI. |
Databáze: | OpenAIRE |
Externí odkaz: | |
Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |