TGF-β1-induced endothelial transcytosis drives blood-brain barrier leakage during aging.

Cheng Fang, Yinzhong Ma, Pengju Wei, Shilun Yang, Min Yu, Jingjing Liu, Sen Suo, Ruoyu Zhao, Yabin Ji, Basharat Hussain, Linhui Qiu, Zhuobo Zhang, Xuhui Chen, Kaihua Lin, Feng Wang, Zhen-Ni Guo, Yi Yang, Junlei Chang

State Key Laboratory of Biomedical Imaging Science and System, Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.State Key Laboratory of Biomedical Imaging Science and System, Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China. · pubmed

Paper

Abstract

Age-related breakdown of the blood-brain barrier (BBB) is associated with cerebrovascular and neurodegenerative diseases, yet its underlying mechanisms remain unclear. Here, we find that BBB leakage begins in midlife and is driven primarily by increased endothelial caveolar transcytosis rather than tight junction disruption. AAV-mediated knockdown of caveolin-1 or restoration of Mfsd2a expression reduces endothelial vesicle formation and BBB leakage in aged mice. Transforming growth factor (TGF)-β1, originating from both brain and systemic circulation, increases with aging and directly suppresses Mfsd2a transcription via the Tgfbr2-Smad2/4 signaling in brain microvascular endothelial cells, thereby promoting caveolar transcytosis and BBB leakage. Endothelial-specific Tgfbr2 knockout or pharmacological inhibition of TGF-β signaling reduces endothelial caveolar transcytosis and BBB leakage and attenuates neurological dysfunction in aged mice. These findings identify TGF-β1-induced endothelial transcytosis as a central mechanism underlying age-related BBB breakdown and offer potential therapeutic targets for preserving brain health in age-related neurovascular disorders.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper identifies TGF-β1-induced endothelial transcytosis as a mechanistic driver of age-related blood-brain barrier breakdown, offering a specific molecular target for intervening in a fundamental aging phenotype. This work is relevant because it addresses a root cause of neurovascular aging rather than just treating downstream symptoms, although the impact is limited by the incremental nature of identifying a known pathway's role in a specific context.

Author of this paper? Send a correction.