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.

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.

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Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6 and Dlx2 expression, in vitro differentiation into neurons expressing GABA and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.Significance StatementHere we demonstrate that porcine MGE, like rodents, exhibit a distinct transcriptional and pallial interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic pallial interneuron origins in the pig, and because a rich neurodevelopmental literature on embryonic mouse MGE exists (with some additional characterizations in other species like monkey and human) our work allows direct neurodevelopmental comparisons with this literature.