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

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2022 · $748,967

## Abstract

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.

## Key facts

- **NIH application ID:** 10345905
- **Project number:** 1R01AG075583-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Bjoern Bauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $748,967
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10345905

## Citation

> US National Institutes of Health, RePORTER application 10345905, Blood-Brain Barrier Repair in Alzheimer’s Disease with Epilepsy (1R01AG075583-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10345905. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*