No 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.

Chheda et al. have identified an HLA-A2–restricted CD8+ T cell epitope encompassing the H3.3K27M mutation and a corresponding TCR that specifically recognizes the H3.3K27M epitope in glioma cells. These data establish a preclinical basis for T cell–based therapy for HLA-A2+ patients with H3.3K27M+ glioma.

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-anddysfunctional 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 lifespan. 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. Specifically, infusion of the serum protein albumin into the young 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. Finally, 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. cm or less), and percentage of time at the novel object was quantified as (duration investigating novel object) / (total duration investigating all three objects). The set objects were chosen from common items such as lab bottles, pipette boxes, cups (placed open-side down), etc., that were of similar dimensions but varied in shape, color, and material. The sequence and position of objects used across trials was identical for all mice.