Blood-Brain Barrier Dysfunction in Alzheimer's Disease: New Mechanistic Insights and Therapeutic Strategies

Aβ and tau accumulation is one hallmark of Alzheimer’s disease (AD) that contributes to neurodegeneration and cognitive decline. We and others have documented that Aβ is a key driver of blood-brain barrier dysfunction. A leaky and dysfunctional barrier, in turn, contributes to AD pathology suggesting a vicious, perpetual feedback loop. Robust evidence points to Aβ as one driver of barrier dysfunction, but little is known about the role of tau, the other signature peptide in AD. We found that tau induces barrier dysfunction, and that tau is transported across the brain endothelium into the capillary lumen. These findings support the conclusion that both Aβ and tau contribute to barrier dysfunction and cognitive decline in AD. However, the mechanism underlying tau- induced barrier dysfunction is unknown, and proteins that clear tau from the brain are also unknown. Thus, therapeutic strategies that repair Aβ/tau-induced barrier dysfunction are not available. In this application, we address this critical unmet need and propose to determine the mechanistic link between tau signaling and barrier dysfunction, to identify tau transport proteins, and to develop a strategy to repair Aβ/tau-induced barrier dysfunction. Our objective in this proposal is to establish a mechanism-based intervention that targets Aβ/tau to treat barrier dysfunction in AD. Based on preliminary data, our central hypothesis is that targeting SIRT1/NOX repairs Aβ/tau-mediated barrier dysfunction and slows cognitive decline in APP/tau models. Our rationale is that this proposed research has the potential to provide a basis for a disease-modifying intervention to successfully treat barrier dysfunction in AD patients. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism responsible for tau-induced barrier leakage. 2) Determine tau transport across the blood-brain barrier. 3) Develop a therapeutic intervention to repair Aβ/tau-induced barrier dysfunction. In Aim 1, we will identify signaling steps through which tau induces barrier dysfunction in isolated brain capillaries from wildtype and KO mice and in isolated human brain capillaries. In Aim 2, we will identify proteins that transport tau across the capillary endothelium in vivo and in human brain capillaries. In Aim 3, we will block Aβ and tau signaling to repair barrier dysfunction and evaluate the benefit of this strategy to slow cognitive decline in two preclinical APP/tau models. The proposed research is innovative because it represents a new and substantive departure from the status quo to a disease-modifying combination therapy focused on both Aβ and tau aimed at new molecular targets to repair barrier dysfunction and slow cognitive decline. The proposed research is significant because it is expected to create a paradigm shift in our understanding of barrier dysfunction in AD and constitute a crucial step toward developing a mechanism-based intervention to repair barrier dysfunction in patients.