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Original Research

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

Kensuke Toyama, Joshua M. Spin, Alicia C. Deng, Ting-Ting Huang, Ke Wei, Markus U. Wagenhäuser, Takuya Yoshino, Huy Nguyen, Joscha Mulorz, Soumajit Kundu, Uwe Raaz, Matti Adam, Isabel N. Schellinger, Ann Jagger, Philip S. Tsao
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https://doi.org/10.1161/ATVBAHA.118.310822
Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.118.310822
Originally published April 12, 2018
Kensuke Toyama
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Joshua M. Spin
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Alicia C. Deng
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Ting-Ting Huang
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Ke Wei
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Markus U. Wagenhäuser
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Takuya Yoshino
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Huy Nguyen
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Joscha Mulorz
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Soumajit Kundu
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Uwe Raaz
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Matti Adam
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Isabel N. Schellinger
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Ann Jagger
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Philip S. Tsao
From the Division of Cardiovascular Medicine (K.T., J.M.S., A.C.D., M.U.W., T.Y., J.M., U.R., M.A., I.N.S., A.J., P.S.T.) and Department of Neurology and Neurological Sciences (T.-T.H., H.N.), Stanford University School of Medicine, CA; and VA Palo Alto Health Care System, CA (K.T., J.M.S., A.C.D., K.W., M.U.W., T.Y., J.M., S.K., U.R., M.A., I.N.S., A.J., P.S.T.).
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Abstract

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.

  • blood–brain barrier
  • dementia
  • microRNA
  • tight junction
  • white matter
  • Received January 4, 2018.
  • Accepted March 19, 2018.
  • © 2018 American Heart Association, Inc.

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    MicroRNA-Mediated Therapy Modulating Blood–Brain Barrier Disruption Improves Vascular Cognitive Impairment
    Kensuke Toyama, Joshua M. Spin, Alicia C. Deng, Ting-Ting Huang, Ke Wei, Markus U. Wagenhäuser, Takuya Yoshino, Huy Nguyen, Joscha Mulorz, Soumajit Kundu, Uwe Raaz, Matti Adam, Isabel N. Schellinger, Ann Jagger and Philip S. Tsao
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.118.310822, originally published April 12, 2018
    https://doi.org/10.1161/ATVBAHA.118.310822

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    MicroRNA-Mediated Therapy Modulating Blood–Brain Barrier Disruption Improves Vascular Cognitive Impairment
    Kensuke Toyama, Joshua M. Spin, Alicia C. Deng, Ting-Ting Huang, Ke Wei, Markus U. Wagenhäuser, Takuya Yoshino, Huy Nguyen, Joscha Mulorz, Soumajit Kundu, Uwe Raaz, Matti Adam, Isabel N. Schellinger, Ann Jagger and Philip S. Tsao
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.118.310822, originally published April 12, 2018
    https://doi.org/10.1161/ATVBAHA.118.310822
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