Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice

Yingxi Wu; Haijian Wu; Jianxiong Zeng; Brock Pluimer; Shirley Dong; Xiaochun Xie; Xinying Guo; Tenghuan Ge; Xinyan Liang; Sudi Feng; Youzhen Yan; Jian-Fu Chen; Naomi Sta Maria; Qingyi Ma; Fernando Gomez-Pinilla; Zhen Zhao

doi:10.1186/s40478-021-01178-7

Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice

Acta Neuropathol Commun. 2021 Apr 23;9(1):74. doi: 10.1186/s40478-021-01178-7.

Authors

Yingxi Wu^#^{1

2}, Haijian Wu^#^{1

2

3}, Jianxiong Zeng^{1

2}, Brock Pluimer^{1

2

4}, Shirley Dong^{1

2}, Xiaochun Xie^{1

2}, Xinying Guo^{1

2}, Tenghuan Ge^{1

2}, Xinyan Liang^{1

2

4}, Sudi Feng^{1

2}, Youzhen Yan^{1

2}, Jian-Fu Chen⁵, Naomi Sta Maria^{1

2}, Qingyi Ma⁶, Fernando Gomez-Pinilla⁷, Zhen Zhao^{8

9

10}

Affiliations

¹ Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Room: 241, 1501 San Pablo Street, Los Angeles, CA, 90033, USA.
² Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
³ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China.
⁴ Neuroscience Graduate Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁵ Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033, USA.
⁶ Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.
⁷ Brain Injury Research Center, Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁸ Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Room: 241, 1501 San Pablo Street, Los Angeles, CA, 90033, USA. zzhao@usc.edu.
⁹ Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. zzhao@usc.edu.
¹⁰ Neuroscience Graduate Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. zzhao@usc.edu.

^# Contributed equally.

Abstract

Introduction: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored.

Methods: In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD.

Results: mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice.

Discussion: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.

Keywords: Alzheimer’s disease; Blood–brain barrier; Microvascular injury; Traumatic brain injury; β-amyloid.

Publication types

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

MeSH terms

Alzheimer Disease / etiology
Alzheimer Disease / genetics
Alzheimer Disease / pathology*
Animals
Brain Concussion / complications
Brain Concussion / genetics
Brain Concussion / pathology*
Cognitive Dysfunction / etiology
Cognitive Dysfunction / genetics
Cognitive Dysfunction / pathology*
Disease Progression*
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microvessels / pathology*

Abstract

Publication types

MeSH terms

Grants and funding