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

Content Provider	Springer Nature : BioMed Central
Author	Li, Jianhua Li, Mengyu Ge, Yangyang Chen, Jiayi Ma, Jiamin Wang, Chenchen Sun, Miaomiao Wang, Li Yao, Shanglong Yao, Chengye
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.
Related Links	https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-022-00807-5.pdf
Ending Page	21
Page Count	21
Starting Page	1
File Format	HTM / HTML
ISSN	20453701
DOI	10.1186/s13578-022-00807-5
Journal	Cell & Bioscience
Issue Number	1
Volume Number	12
Language	English
Publisher	BioMed Central
Publisher Date	2022-05-26
Access Restriction	Open
Subject Keyword	Cell Biology Microbiology Stem Cells Neurobiology Proteomics Alzheimer’s disease Blood–brain barrier Pericytes Fatty acid transporter Beta-amyloid Mitophagy Ferroptosis
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7/2023

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