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miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy.
Chen, Chien-Yuan; Chao, Yung-Mei; Lin, Hsiu-Fen; Chen, Chao-Jung; Chen, Cheng-Sheng; Yang, Jenq-Lin; Chan, Julie Y H; Juo, Suh-Hang H.
Afiliação
  • Chen CY; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Chao YM; Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
  • Lin HF; Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • Chen CJ; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Chen CS; Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
  • Yang JL; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
  • Chan JYH; Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • Juo SH; Department of Psychiatry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Aging Cell ; 19(11): e13236, 2020 11.
Article em En | MEDLINE | ID: mdl-33029941
ABSTRACT
Blood-brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR-195 provides vasoprotection, which urges us to explore the role of miR-195 in BBB integrity. Here, we found cerebral miR-195 levels decreased with age, and BBB leakage was significantly increased in miR-195 knockout mice. Furthermore, exosomes from miR-195-enriched astrocytes increased endothelial TJ proteins and improved BBB integrity. To decipher how miR-195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic-lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR-195-suppressed thrombospondin-1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin-5-p62 and ZO1-p62 complexes in cerebral ECs while TSP1 impaired general autophagy. Delivering TSP1 antibody into the circulation showed dose-dependent reduction of BBB leakage by 20%-40% in 25-month-old mice. Intravenous or intracerebroventricular injection of miR-195 rescued TSP1-induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage (p = 0.0015), while the normal subjects had the lowest TSP1 (p < 0.0001). Taken together, the study implies that TSP1-regulated selective autophagy facilitates the degradation of TJ proteins and weakens BBB integrity. An adequate level of miR-195 can suppress the autophagy-lysosome pathway via a reduction of TSP1, which may be important for maintaining BBB function.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Trombospondina 1 / MicroRNAs Limite: Animals Idioma: En Revista: Aging Cell Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Trombospondina 1 / MicroRNAs Limite: Animals Idioma: En Revista: Aging Cell Ano de publicação: 2020 Tipo de documento: Article