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Breaking barriers in aging and disease
The blood-brain barrier (BBB) regulates the communication between the vasculature and the brain. Aging and neurological disorders have been associated with BBB defects. Now, Milikovsky et al. and Senatorov et al. studied the consequences of BBB impairments in aging and disease. Milikovsky et al. found that in patients with epilepsy or Alzheimer’s disease, as well as in aging mice, BBB impairments were spatially associated with transient electroencephalographic abnormalities. Senatorov et al. extended the study at the molecular level, showing that BBB breakdown triggered transforming growth factor–β (TGFβ) signaling in astrocytes and cognitive impairments in aging rodents. Similar abnormalities were also found in brain tissue from aging individuals. TGFβ inhibition in aged mice reversed the pathological phenotype.
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.
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