| First Author | Senatorov VV Jr | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 521 | PubMed ID | 31801886 |
| Mgi Jnum | J:283564 | Mgi Id | MGI:6385818 |
| Doi | 10.1126/scitranslmed.aaw8283 | Citation | Senatorov VV Jr, et al. (2019) Blood-brain barrier dysfunction in aging induces hyperactivation of TGFbeta signaling and chronic yet reversible neural dysfunction. Sci Transl Med 11(521) |
| abstractText | 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-beta (TGFbeta) 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 TGFbeta signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFbeta receptors or pharmacological inhibition of TGFbeta 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 TGFbeta signaling. |
