MicroRNA-Mediated Therapy Modulating Blood–Brain Barrier Disruption Improves Vascular Cognitive Impairment

Autor: Philip S. Tsao, Ann Jagger, Joshua M. Spin, Soumajit Kundu, Isabel N. Schellinger, Takuya Yoshino, Joscha Mulorz, Matti Adam, Alicia C. Deng, Huy Nguyen, Kensuke Toyama, Ting-Ting Huang, Uwe Raaz, Markus U. Wagenhäuser, Ke Wei
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Prevention of dementia
Blood–brain barrier
Tight Junctions
Capillary Permeability
03 medical and health sciences
Cognition
0302 clinical medicine
Occludin
Gene expression
microRNA
Electric Impedance
medicine
Animals
Humans
Dementia
Claudin-5
Cognitive impairment
3' Untranslated Regions
Binding Sites
Behavior
Animal
Tight junction
Tumor Necrosis Factor-alpha
business.industry
Genetic Therapy
Oligonucleotides
Antisense
medicine.disease
Mice
Inbred C57BL
Cerebrovascular Disorders
Disease Models
Animal
MicroRNAs
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
Blood-Brain Barrier
Zonula Occludens-1 Protein
Blood-brain barrier disruption
Cognition Disorders
Cardiology and Cardiovascular Medicine
business
Neuroscience
030217 neurology & neurosurgery
Zdroj: Arteriosclerosis, Thrombosis, and Vascular Biology. 38:1392-1406
ISSN: 1524-4636
1079-5642
DOI: 10.1161/atvbaha.118.310822
Popis: Objective— There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood–brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood–brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment. Approach and Results— Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3′-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid –modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood–brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery. Conclusions— We here provide the first evidence that the TNFα–miR-501-3p–ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion–induced working memory deficits and white matter lesions, as a result of blood–brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.
Databáze: OpenAIRE
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