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

超过25%的阿尔茨海默病(AD)患者合并癫痫。阿尔茨海默病合并癫痫 (ADxEpi)，与单独使用AD相比，癫痫发作会加速认知能力下降，并进一步减少预期寿命。一 阿尔茨海默病和癫痫的特征都是血脑屏障功能障碍。我们发现屏障功能障碍是 与无癫痫发作的AD患者相比，ADxEpi患者病情更为严重。总的来说，我们的数据表明， 抗体和癫痫释放的谷氨酸(Aβ/Glu)的结合触发了一个双重正反馈环路，该环路可刺激癫痫发作。 在ADxEpi中消除屏障功能障碍、癫痫发作和认知能力下降。但是，详细的机制(S)， ADxEpi患者导致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的下降。这一知识鸿沟代表着一种至关重要的 未得到满足的需求，这将阻止我们实现ADxEpi患者的治疗进展。我们的总体目标 本应用的目的是定义ADxEpi中屏障功能障碍的基础机制，并开发一种 治疗性干预。根据初步数据，中心假设是阻断Aβ/谷氨酸信号- ING可修复屏障功能障碍，减轻癫痫发作负担，减缓伴有癫痫的AD患者的认知衰退。这个 这项拟议研究的基本原理是，它的完成将为一种新的治疗干预提供基础。 成功治疗ADxEpi患者。这一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)明确屏障之间的关系 阿尔茨海默病合并癫痫患者的功能障碍、认知和癫痫发作3)开发一种治疗干预措施，重新- 阿尔茨海默病合并癫痫患者的屏障功能障碍。在目标1中，我们将确定导致β/Glu- 介导的神经血管炎症和屏障渗漏在分离的小鼠脑毛细血管中的作用及验证 活体内的发现。在目标2中，我们将确定ADxEpi患者脑组织中的屏障功能障碍及其相互关系 屏障功能障碍程度与癫痫发作负担和患者认知评分的关系。在目标3中，我们将制定一个 旨在修复屏障功能障碍的介入疗法，我们将评估这种干预的好处 在两个啮齿动物ADxEpi模型中。这项拟议的研究具有创新性，因为它代表了一项实质性的突破 从现状将重点从传统的抗癫痫药物转向靶向分子途径 修复屏障功能障碍，从而改善癫痫负担，减缓ADxEpi的认知功能下降。支持- 提出的研究具有重要意义，因为它蕴含着一种新的治疗方法的前景，这种方法具有 临床应用的潜力，以促进ADxEpi患者的治疗。

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.