Mechanisms and treatment of blood-brain barrier dysfunction and related pathology during aging

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the causes of the transition from a “young-and-healthy” to “aged-and-dysfunctional” brain are not well understood. The following studies all address the mechanisms by which the blood-brain barrier (BBB) declines during aging, and how genetic and pharmacological inhibition of inflammatory signaling ameliorates aging-related neuropathology. Chapter 2 describes how the blood-brain barrier (BBB) deteriorates during aging, starting as early as middle age and continuing to the end of the lifespan. This vascular damage activates inflammatory transforming growth factor β (TGFβ) signaling in astrocytes. Using gain-of-function and loss-of-function manipulations in mice, we show that astrocytic TGFβ signaling is necessary and sufficient to cause neural dysfunction and pathological outcomes, including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, inhibition of TGFβ signaling reverses these symptomatic hallmarks of aging. Chapter 3 delves deeper into the mechanism by which molecular correlates of neurosynaptic transmission become dysregulated during aging, focusing specifically on how TGFβ signaling contributes to aging-related cognitive decline via selective remodeling of glutamatergic and GABAergic receptor subunits. Chapter 4 investigates the core mechanism of decline of the transcriptional machinery that governs BBB permeability during aging, and also explores the potential of a novel pharmacological approach aimed at restoring the structural and functional integrity of the BBB. Together, these studies reveal the neurovascular unit as one of the earliest triggers of neurological aging, indicating that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition against TGFβ signaling