Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Xiaoxin Cheng; Yiyan Zheng; Ping Bu; Xiangbei Qi; Chunling Fan; Fengqiao Li; Dong H Kim; Qilin Cao

doi:10.1016/j.expneurol.2017.10.014

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Exp Neurol. 2018 Jan;299(Pt A):97-108. doi: 10.1016/j.expneurol.2017.10.014. Epub 2017 Oct 19.

Authors

Xiaoxin Cheng¹, Yiyan Zheng², Ping Bu², Xiangbei Qi³, Chunling Fan⁴, Fengqiao Li⁵, Dong H Kim², Qilin Cao⁶

Affiliations

¹ The Vivian L Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Cell Biology, Dalian Medical University, 25 Jinxin Road, Dalian, Liaoning 116033, China.
² The Vivian L Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ The Vivian L Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Orthopaedic Trauma Center, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, China.
⁴ The Vivian L Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410011, China.
⁵ Cognosci Inc., Research Triangle Park, NC, USA.
⁶ The Vivian L Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: qi-lin.cao@uth.tmc.edu.

Abstract

Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE^-/-) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE^-/- mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE^-/- mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE^-/- mice. At 42days after injury, the inflammation was still robust in the injured spinal cord in apoE^-/- but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE^-/- mice. The spared white matter was significantly decreased in apoE^-/- mice compared to wild type ones. Locomotor function was significantly decreased in apoE^-/- mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE^-/- mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE^-/- mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

Keywords: Apolipoprotein E; Neuroprotection; Spinal cord injury; Spinal cord-blood-barrier; Treatment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoproteins E / drug effects*
Apolipoproteins E / genetics*
Apoptosis / drug effects
Blood-Air Barrier
Inflammation / pathology
Leukocyte Common Antigens
Locomotion
Lymphocytes / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / pathology
Neuropeptides / therapeutic use
Neuroprotection / drug effects*
Neuroprotection / genetics
Oligodendroglia / pathology
Recovery of Function / drug effects
Spinal Cord Injuries / drug therapy*
Spinal Cord Injuries / genetics*
Spinal Cord Injuries / pathology
White Matter / pathology

Substances

Apolipoproteins E
Neuropeptides
Leukocyte Common Antigens

Grants and funding

R01 NS099635/NS/NINDS NIH HHS/United States