β-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood-brain barrier destruction in Alzheimer's disease

Jianhua Li; Mengyu Li; Yangyang Ge; Jiayi Chen; Jiamin Ma; Chenchen Wang; Miaomiao Sun; Li Wang; Shanglong Yao; Chengye Yao

doi:10.1186/s13578-022-00807-5

β-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood-brain barrier destruction in Alzheimer's disease

Cell Biosci. 2022 May 26;12(1):69. doi: 10.1186/s13578-022-00807-5.

Authors

Jianhua Li^#^{1

2

3}, Mengyu Li^#^{1

2}, Yangyang Ge^{1

2}, Jiayi Chen^{1

2}, Jiamin Ma^{1

2}, Chenchen Wang^{1

2}, Miaomiao Sun^{1

2}, Li Wang^{1

2}, Shanglong Yao^{1

2}, Chengye Yao^#⁴

Affiliations

¹ Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
² Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
³ Department of Critical Care Medicine, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi, 832000, China.
⁴ Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. yaochengye@hust.edu.cn.

^# Contributed equally.

Abstract

Introduction: Blood-brain barrier (BBB) dysfunction may occur at the onset of Alzheimer's disease (AD). Pericytes are a vital part of the neurovascular unit and the BBB, acting as gatekeepers of the BBB. Amyloid β (Aβ) deposition and neurofibrillary tangles in the brain are the central pathological features of AD. CD36 promotes vascular amyloid deposition and leads to vascular brain damage, neurovascular dysfunction, and cognitive deficits. However, the molecular mechanism by which pericytes of the BBB are disrupted remains unclear.

Objectives: To investigate the effect of low-dose Aβ1-40 administration on pericyte outcome and the molecular mechanism of BBB injury.

Methods: We selected 6-month-old and 9-month-old APP/PS1 mice and wild-type (WT) mice of the same strain, age, and sex as controls. We assessed the BBB using PET/CT. Brain pericytes were extracted and cocultured with endothelial cells (bEnd.3) to generate an in vitro BBB model to observe the effect of Aβ1-40 on the BBB. Furthermore, we explored the intracellular degradation and related molecular mechanisms of Aβ1-40 in cells.

Results: BBB permeability and the number of pericytes decreased in APP/PS1 mice. Aβ1-40 increased BBB permeability in an in vivo model and downregulated the expression of CD36, which reversed the Aβ-induced changes in BBB permeability. Aβ1-40 was uptaked in pericytes with high CD36 expression. We observed that this molecule inhibited pericyte proliferation, caused mitochondrial damage, and increased mitophagy. Finally, we confirmed that Aβ1-40 induced pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway.

Conclusion: PDGFRβ (a marker of pericytes), CD36, and Aβ colocalized in vitro and in vivo, and Aβ1-40 caused BBB disruption by upregulating CD36 expression in pericytes. The mechanism by which Aβ1-40 destroys the BBB involves the induction of pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway.

Keywords: Alzheimer’s disease; Beta-amyloid; Blood–brain barrier; Fatty acid transporter; Ferroptosis; Mitophagy; Pericytes.

Grants and funding

81801204/Young Scientists Fund