Blood-Brain Barrier Repair in Alzheimer's Disease with Epilepsy

Epilepsy is an underestimated comorbidity in Alzheimer’s disease (AD) that accelerates cognitive decline and further reduces life expectancy. One hallmark of both AD and epilepsy is blood-brain barrier dysfunction. Two key characteristics of barrier dysfunction in AD and epilepsy are 1) neurovascular inflammation and 2) barrier leakage. Despite increasing evidence supporting that seizures aggravate barrier dysfunction in AD and that cog- nitive decline is accelerated in AD patients with epilepsy, knowledge of the underlying mechanisms remains unknown. Moreover, therapeutic options to repair barrier dysfunction are currently not available. Thus, there is a critical and unmet need to determine the mechanism(s) through which seizures exacerbate barrier dysfunction in AD and to develop strategies to repair barrier dysfunction. Absent such strategies, achieving therapeutic ad- vances in AD patients with epilepsy will remain a challenge. Our overall objective in this application is to develop a therapeutic intervention to repair barrier dysfunction in AD with epilepsy. Based on preliminary data, the central hypothesis is that seizures exacerbate neurovascular inflammation and barrier leakage in AD and that therapeu- tic intervention targeting Aβ/glutamate signaling repairs barrier dysfunction, reduces seizure burden, and slows cognitive de-cline in AD with epilepsy. The rationale for the proposed research is that successful completion will provide a robust framework for the development and clinical translation of a novel evidence-based therapeutic intervention to treat AD patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism responsible for Aβ/glutamate-mediated barrier dysfunction. 2) Define the relation be- tween barrier dysfunction, cognition and seizures in AD patients with epilepsy. 3) Develop a therapeutic inter- vention that repairs barrier dysfunction in AD with epilepsy. In Aim 1, we will determine signaling steps that lead to Aβ/glutamate-mediated neurovascular inflammation and barrier leakage in isolated mouse and human capil- laries ex vivo, and we will verify these findings in vivo. In Aim 2, we will determine the degree of barrier dysfunc- tion in brain tissue from AD patients with epilepsy and to correlate these values with seizure burden and patient cognitive scores. In Aim 3, we will develop an intervention therapy designed to repair barrier dysfunction, and we will evaluate the benefit of this strategy on reducing seizure burden and slowing cognitive decline in two rodent AD models with epilepsy. The proposed research is innovative because it represents a substantive de- parture from the status quo by shifting the focus to molecular targets at the blood-brain barrier to repair barrier dysfunction, improve seizure burden, and slow cognitive decline. The proposed research is significant because it holds the promise of a novel therapeutic approach to repair barrier dysfunction that has translational potential for clinical use to advance treatment of AD patients with epilepsy.