Leaky blood-brain barrier triggers neural dysfunction that is reversible

As human life expectancy extends, the challenge of neural dysfunction as part of aging, not to mention that associated with dementia-related disorders, continues to grow. Though there have been significant advances in understanding the differences between young, functionally healthy and older, cognitively-impaired brains, there remains no identified mechanism for how this transition may occur. Now, in an exciting Science Translational Medicine paper, Senatorov et al. identify the progressive, age-dependent breakdown of the blood-brain barrier (BBB) as the trigger for subsequent neural pathology and pathophysiology (1). The authors’ central premise was derived from their elegant use of molecular, electrophysiological, and behavioral techniques on rodents as well as imaging and postmortem histology on humans. They report that BBB dysfunction allows leaking of albumin (and other factors like fibrinogen) out of the cerebral capillaries where it activates TGFβ signaling in astrocytes. Both gain-of-function and loss-of-function assays were utilized to establish that activated astrocytes release inflammatory mediators that lead to glial scarring and neural circuitry compromise that manifests as hyperexcitability and functional abnormalities. Intriguingly, genetic or pharmacological inhibition of this signaling reversed these effects, essentially preserving or restoring “young brain” network features and cognitive capabilities. Thus, the researchers have pinpointed astrocyte TGFβ signaling as a potential culprit for age-related cognitive decline and disease, and offered tantalizing evidence that this pathway can be pharmacologically reversed.

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