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

阿尔茨海默病伴癫痫的血脑屏障修复

• 批准号: 10345905
• 负责人: Bjoern Bauer
• 金额: $ 74.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345905
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Attenuated; Blood - brain barrier anatomy; Brain; Characteristics; Clinical; Clinical Data; Cognition; Cyclooxygenase Inhibitors; Data; Disease Progression; Epilepsy; Extravasation; Feedback; Functional disorder; Glutamates; Health; Impaired cognition; Inflammation; Intervention; Knowledge; LOX gene; Lead; Life Expectancy; Link; Matrix Metalloproteinases; Mediating; Mission; Modeling; Molecular Target; Mus; National Institute of Neurological Disorders and Stroke; Outcome; Oxidative Stress; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Process; Public Health; Research; Rodent; Seizures; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; United States National Institutes of Health; Work; base; brain tissue; cerebral capillary; comorbidity; design; glutamatergic signaling; improved; in vivo; innovation; nervous system disorder; neurovascular; novel therapeutic intervention; pre-clinical; prevent; repaired; success; therapy design; translational potential; vascular inflammation

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.

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.