Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction

Vladimir V. Senatorov, Aaron R. Friedman, Dan Z. Milikovsky, Jonathan Ofer, Rotem Saar-Ashkenazy, Adiel Charbash, Naznin Jahan, Gregory Chin, Eszter Mihaly, Jessica M. Lin, Harrison J. Ramsay, Ariana Moghbel, Marcela K. Preininger, Chelsy R. Eddings, Helen V. Harrison, Rishi Patel, Yizhuo Shen, Hana Ghanim, Huanjie Sheng, Ronel VekslerPeter H. Sudmant, Albert Becker, Barry Hart, Michael A. Rogawski, Andrew Dillin, Alon Friedman, Daniela Kaufer

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor–β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

Original languageEnglish (US)
Article numbereaaw8283
JournalScience Translational Medicine
Volume11
Issue number521
DOIs
StatePublished - Dec 4 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Senatorov, V. V., Friedman, A. R., Milikovsky, D. Z., Ofer, J., Saar-Ashkenazy, R., Charbash, A., Jahan, N., Chin, G., Mihaly, E., Lin, J. M., Ramsay, H. J., Moghbel, A., Preininger, M. K., Eddings, C. R., Harrison, H. V., Patel, R., Shen, Y., Ghanim, H., Sheng, H., ... Kaufer, D. (2019). Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction. Science Translational Medicine, 11(521), [eaaw8283]. https://doi.org/10.1126/scitranslmed.aaw8283