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
基本信息
- 批准号:10345905
- 负责人:
- 金额:$ 74.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloid beta-ProteinAttenuatedBlood - brain barrier anatomyBrainCharacteristicsClinicalClinical DataCognitionCyclooxygenase InhibitorsDataDisease ProgressionEpilepsyExtravasationFeedbackFunctional disorderGlutamatesHealthImpaired cognitionInflammationInterventionKnowledgeLOX geneLeadLife ExpectancyLinkMatrix MetalloproteinasesMediatingMissionModelingMolecular TargetMusNational Institute of Neurological Disorders and StrokeOutcomeOxidative StressPathway interactionsPatientsPersonal SatisfactionPharmaceutical PreparationsProcessPublic HealthResearchRodentSeizuresSignal TransductionTestingTherapeuticTherapeutic InterventionTight JunctionsUnited States National Institutes of HealthWorkbasebrain tissuecerebral capillarycomorbiditydesignglutamatergic signalingimprovedin vivoinnovationnervous system disorderneurovascularnovel therapeutic interventionpre-clinicalpreventrepairedsuccesstherapy designtranslational potentialvascular inflammation
项目摘要
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Bjoern Bauer其他文献
Bjoern Bauer的其他文献
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{{ truncateString('Bjoern Bauer', 18)}}的其他基金
Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy
CBD修复癫痫血脑屏障功能障碍的机制和治疗潜力
- 批准号:
10644405 - 财政年份:2023
- 资助金额:
$ 74.9万 - 项目类别:
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:
10613906 - 财政年份:2022
- 资助金额:
$ 74.9万 - 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
- 批准号:
10225435 - 财政年份:2018
- 资助金额:
$ 74.9万 - 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
- 批准号:
9761586 - 财政年份:2018
- 资助金额:
$ 74.9万 - 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
- 批准号:
10452766 - 财政年份:2018
- 资助金额:
$ 74.9万 - 项目类别:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy
解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略
- 批准号:
10380864 - 财政年份:2012
- 资助金额:
$ 74.9万 - 项目类别:
Blood-brain barrier function in epilepsy: new targets for therapy
癫痫中的血脑屏障功能:治疗的新目标
- 批准号:
8687756 - 财政年份:2012
- 资助金额:
$ 74.9万 - 项目类别:
Blood-brain barrier function in epilepsy: new targets for therapy
癫痫中的血脑屏障功能:治疗的新目标
- 批准号:
8887163 - 财政年份:2012
- 资助金额:
$ 74.9万 - 项目类别:
Blood-brain barrier function in epilepsy: new targets for therapy
癫痫中的血脑屏障功能:治疗的新目标
- 批准号:
9107249 - 财政年份:2012
- 资助金额:
$ 74.9万 - 项目类别:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy
解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略
- 批准号:
9976832 - 财政年份:2012
- 资助金额:
$ 74.9万 - 项目类别: