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[191212 Àú³Î¹ßÇ¥] Blood-brain barrier dysfunction in aging induces hyperactivation of TGF¥â signaling and chronic yet reversible neural dysfunction

ÃÖÇöÁ¤ ¦¢ 2019-12-11

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 2019 Dec 4;11(521). pii: eaaw8283. doi: 10.1126/scitranslmed.aaw8283.


Blood-brain barrier dysfunction in aging induces hyperactivation of TGF¥â signaling and chronic yet reversible neural dysfunction.


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-¥â (TGF¥â) 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 TGF¥â signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGF¥â receptors or pharmacological inhibition of TGF¥â 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 TGF¥â signaling.




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