UC Berkeley

Blood-brain barrier dysfunction (BBBD) and accumulation of senescent astrocytes occur in the hippocampus during brain aging and contribute to cognitive decline, neural dysfunction, and neurodegeneration. In this work, I advance our understanding of the relationship between these events. In chapter one, I describe the vital role astrocytes play in maintaining brain homeostasis and the various functions they perform in the healthy brain. I also summarize known mechanisms by which astrocytes mediate neuropathology. Given the salience of transforming growth factor beta 1 (TGFβ) signaling in aging phenotypes and neural dysfunction, I conclude that BBBD-induced TGFβ hyperactivation should be explored as a potential mechanistic link between BBBD and senescence in the brain. In chapter two, I test the hypothesis that chronic exposure to BBBD-associated serum albumin can induce stress-induced premature senescence (SIPS) in astrocytes via TGFβ hyperactivation. To this end, I utilized an in vivo model of BBBD in which albumin was continuously infused into the lateral ventricles of adult mice. Prolonged albumin exposure significantly increased TGFβ activation and the burden of senescent astrocytes in hippocampal tissue. Pharmacological inhibition of the type I TGFβ receptor (TGFβR) ALK5 or conditional genetic knockdown of astrocytic TGFβR prior to albumin infusion was sufficient to prevent albumin-induced astrocyte senescence. Since I observed TGFβ-dependent astrocyte senescence in the albumin infusion model of BBBD, I sought to determine whether senescence was also implicated in the etiology of repetitive mild traumatic brain injury (rmTBI). In chapter 3, I utilized a novel closed-head injury model of rmTBI in which a single injury results in brief loss of consciousness and acute transient neurological symptoms. Five days of injuries resulted in diffuse BBBD and increased activation of TGFβ signaling and senescence markers that were associated with behavioral disinhibition. rmTBI mice also experienced enduring deficits in learning and memory retention. Together, these results establish a link between TGFβ signaling activation and cellular senescence and suggest that BBBD can trigger these phenotypic changes. In chapter 4, I conclude by offering my perspectives on BBBD, TGFβ signaling, and cellular senescence in neuropathology, and provide future directions for inquiry in the field.