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

Award Number: R01AG075583
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Blood-Brain Barrier Repair in Alzheimer’s Disease with Epilepsy - More than 25% of patients with Alzheimer’s disease (AD) develop epilepsy as 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 (Aβ/Glu) triggers a dual positive feedback loop which exac- erbates barrier dysfunction, seizures, and cognitive decline in ADxEpi. However, the detailed mechanism(s) that leads 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 Aβ/glutamate signal- ing 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 Aβ/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 re- pairs barrier dysfunction in AD with epilepsy. In Aim 1, we will determine signaling steps that lead to Aβ/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 pro- posed 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $715,380 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	4	6/16/2025	NON-COMPETING CONTINUATION	$58,395
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	4	5/2/2025	NON-COMPETING CONTINUATION	$656,985
														Subtotal = $715,380

Issue Date FY: 2024 ( Subtotal = $739,698 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	5/15/2024	NON-COMPETING CONTINUATION	$739,698
														Subtotal = $739,698

Issue Date FY: 2023 ( Subtotal = $701,657 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	2	5/4/2023	NON-COMPETING CONTINUATION	$701,657
														Subtotal = $701,657

Issue Date FY: 2022 ( Subtotal = $748,967 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	4/26/2022	NEW	$748,967
														Subtotal = $748,967

Grand Total All Awards = $2,905,702

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

Award Number: R01AG075583

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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