脉络丛损伤导致Aβ清除代谢障碍、神经生长因子分泌和中枢免疫调节失衡，是触发和恶化阿尔茨海默症（Alzheimer’s Disease，AD）的重要病理事件。如何调控脉络丛稳态是AD治疗的潜在重要突破口之一。我们前期发现AD模型小鼠脉络丛出现Aβ堆积与脉络丛微血管损伤密切相关。本项目将围绕AD病理进程中脉络丛微血管损伤的潜在分子机制及其对脉络丛稳态调控依次展开：(1) 考察AD进程中脉络丛损伤的变化规律，揭示脉络丛微血管损伤是介导脉络丛功能异常的重要病理因素；(2) 考察脉络丛血管损伤过程中HtrA2关联信号变化规律及其与硝化应激的内在转导机制，揭示AD病理进程中脉络丛损伤的重要触发环节及调控模式；(3) 探讨以脉络丛微血管HtrA2硝基化修饰为靶点的调控干预对脉络丛功能稳态及AD病理进程的改善作用。可望为研发AD防治药物提供新的研究思路和潜在“靶标”分子。

Alzheimer’s Disease is a neurodegenerative disorder characterized with the key pathogenic factor Amyloid-β accumulation. Multiple lines of evidence suggest that cerebral choroid plexus dysfunction contributes to failure of Aβ clearance and ultimate disease escalation, which raises a question how to regulate and maintain the choroid plexus physiological function. Here we focus on Aβ-induced choroid plexus vascular dysfunction and underlying mechanism，which，in turn，impair the choroid plexus activity and augment AD progression. The present study demonstrate that Aβ-induced injury in choroid plexus vessel contributes to the choroid plexus nitrosative damage in AD pathology, which is mediated by the nitration of HtrA2 in vascular endothelial cells. Regulation of endothelial HtrA2 signaling in choroid plexus counteracts the cerebral choroid plexus dysfunction and dementia mitigation in AD pathology. These findings shed a new light on the downstream mechanism responsible for Aβ-induced choroid plexus dysfunction and raised a possibility that targeting HtrA2 signaling-mediated vascular dysfunction for AD treatment.