[191212 저널발표] Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction
최현정 │ 2019-12-11
Sci Transl Med. 2019 Dec 4;11(521). pii: eaaw8283. doi: 10.1126/scitranslmed.aaw8283.
Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction.
Senatorov VV Jr1,2, Friedman AR1,2, Milikovsky DZ3, Ofer J3, Saar-Ashkenazy R3, Charbash A3, Jahan N2,4, Chin G4, Mihaly E5, Lin JM2, Ramsay HJ2, Moghbel A4, Preininger MK4, Eddings CR4, Harrison HV6, Patel R4, Shen Y4, Ghanim H4, Sheng H2, Veksler R3, Sudmant PH2, Becker A7, Hart B8, Rogawski MA9, Dillin A10, Friedman A3,11, Kaufer D12,2,13.
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.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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