Friday, May 9, 2025
5/9/2025
Blood-Brain Barrier Dysfunction in Alzheimer’s Disease: New Mechanistic Insights and Therapeutic Strategies - Amyloid β (Aβ) is a key driver of blood-brain barrier dysfunction in Alzheimer’s disease (AD). A leaky and dysfunctional barrier, in turn, contributes to AD pathology and cognitive decline. In addition to Aβ, another key driver of AD pathology is microtubule-associated protein tau (tau). In AD, intracellular tau accumulates in neurons, contributing to neurodegeneration and cognitive decline. Tau also exists as extracellular tau, which activates various signaling pathways. Importantly, elevated extracellular tau contributes to neurodegeneration and cognitive decline. We found that extracellular tau induces barrier dysfunction and is transported across the brain capillary endothelium into the vascular 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 tau transport has not been described. 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, define tau transport at the blood-brain barrier, and develop a strategy to repair Aβ/tau-induced barrier dysfunction. Our objective in this proposal is to establish a mechanism-based intervention targeting 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 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 dysfunction. 2) Determine tau transport across the blood-brain barrier. 3) Develop a therapeutic intervention to repair Ab/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 define tau transport across the capillary endothelium in vivo and in human brain capillaries. In Aim 3, we will block Ab 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.
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