R01AG075583

Blood-Brain Barrier Repair in Alzheimer's Disease with Epilepsy - More than 25% of patients with Alzheimer's disease (AD) develop epilepsy as a co-morbidity. In AD with epilepsy (ADXEPI), seizures accelerate cognitive decline and further reduce life expectancy compared to AD alone. One hallmark of both AD and epilepsy is blood-brain barrier dysfunction. We discovered that barrier dysfunction is more severe in ADXEPI patients compared to seizure-free AD patients. Collectively, our data suggest that a combination of AB and seizure-released glutamate (ASS/GLU) triggers a dual positive feedback loop which exacerbates barrier dysfunction, seizures, and cognitive decline in ADXEPI. However, the detailed mechanism(s) that lead to barrier dysfunction in ADXEPI is/are unknown, and treatment options for ADXEPI patients are limited to anti-seizure drugs that by themselves accelerate cognitive decline. This knowledge gap represents a critical and unmet need which will prevent us from achieving therapeutic advances for ADXEPI patients.

Our overall objective in this application is to define the mechanism that underlies barrier dysfunction in ADXEPI and to develop a therapeutic intervention. Based on preliminary data, the central hypothesis is that blocking ASS/GLUTAMATE signaling repairs barrier dysfunction, reduces seizure burden, and slows cognitive decline in AD with epilepsy. The rationale for the proposed research is that its completion will provide the basis for a novel therapeutic intervention to successfully treat ADXEPI patients. The hypothesis will be tested by pursuing three specific aims:

1) Identify the mechanism responsible for ASS/GLUTAMATE-mediated barrier dysfunction.
2) Define the relation between barrier dysfunction, cognition, and seizures in AD patients with epilepsy.
3) Develop a therapeutic intervention that repairs barrier dysfunction in AD with epilepsy.

In Aim 1, we will determine signaling steps that lead to ASS/GLU-mediated neurovascular inflammation and barrier leakage in isolated mouse brain capillaries and verify these findings in vivo. In Aim 2, we will determine barrier dysfunction in brain tissue from ADXEPI patients and correlate the degree of barrier dysfunction with seizure burden and patient cognition scores. In Aim 3, we will develop an intervention therapy designed to repair barrier dysfunction, and we will evaluate the benefit of this intervention in two rodent ADXEPI models.

The proposed research is innovative because it represents a substantive departure from the status quo by shifting the focus from traditional anti-seizure drugs to targeting molecular pathways to repair barrier dysfunction, thereby improving seizure burden, and slowing cognitive decline in ADXEPI. The proposed research is significant because it holds the promise of a new therapeutic approach that has translational potential for clinical use to advance the treatment of ADXEPI patients.

University Of Kentucky Research Foundation

NOT APPLICABLE

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Lexington, Kentucky 405060004 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $748,967 to $3,625,092.