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
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