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.

超过 25% 的阿尔茨海默病 (AD) 患者合并有癫痫。患有癫痫的AD (ADxEpi)，与单独的 AD 相比，癫痫发作会加速认知能力下降并进一步缩短预期寿命。一 AD 和癫痫的特点是血脑屏障功能障碍。我们发现屏障功能障碍 与无癫痫发作的 AD 患者相比，ADxEpi 患者的病情更为严重。总的来说，我们的数据表明 Ab 和癫痫释放的谷氨酸 (Aβ/Glu) 的组合会触发双重正反馈循环，从而使 缓解 ADxEpi 的屏障功能障碍、癫痫发作和认知能力下降。然而，详细的机制 导致 ADxEpi 屏障功能障碍的原因尚不清楚，ADxEpi 患者的治疗选择仅限于 抗癫痫药物本身会加速认知能力下降。这种知识差距代表了一个关键和 未满足的需求将阻止我们在 ADxEpi 患者的治疗方面取得进展。我们的总体目标 本申请的目的是定义 ADxEpi 屏障功能障碍的机制，并开发一种 治疗干预。根据初步数据，中心假设是阻断 Aβ/谷氨酸信号- 修复屏障功能障碍，减轻癫痫发作负担，并减缓 AD 癫痫患者的认知能力下降。这 拟议研究的基本原理是，其完成将为新型治疗干预提供基础 成功治疗 ADxEpi 患者。该假设将通过追求三个具体目标来检验：1）确定 Aβ/谷氨酸介导的屏障功能障碍的机制。 2）定义barrier之间的关系 AD 癫痫患者的功能障碍、认​​知和癫痫发作。 3) 制定治疗干预措施 将 AD 中的屏障功能障碍与癫痫配对。在目标 1 中，我们将确定导致 Aβ/Glu- 的信号传导步骤 介导离体小鼠脑毛细血管的神经血管炎症和屏障渗漏并验证这些 体内发现。在目标 2 中，我们将确定 ADxEpi 患者脑组织中的屏障功能障碍，并将 屏障功能障碍的程度与癫痫发作负担和患者认知评分有关。在目标 3 中，我们将开发一个 旨在修复屏障功能障碍的干预疗法，我们将评估这种干预的益处 在两个啮齿动物 ADxEpi 模型中。拟议的研究具有创新性，因为它代表了实质性的偏离 改变现状，将重点从传统的抗癫痫药物转向针对分子途径 修复屏障功能障碍，从而改善 ADxEpi 的癫痫发作负担并减缓认知能力下降。亲 所提出的研究意义重大，因为它有望提供一种具有转化作用的新治疗方法 具有临床应用推进 ADxEpi 患者治疗的潜力。