THE ROLE OF ZFYVE21 IN CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER'S DISEASE

ZFYVE21 在阿尔茨海默病脑淀粉样血管病中的作用

• 批准号: 10288327
• 负责人: DANIEL JANE-WIT
• 金额: $ 38.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288327
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Arteries; Attenuated; Biological Assay; Biological Models; Biology; Biopsy; Blood Vessels; Brain; Cell membrane; Cerebral Amyloid Angiopathy; Cerebrovascular system; Cerebrum; Chronic; Complement; Complement Activation; Complement Membrane Attack Complex; Complement Suppression; Data; Dementia; Deposition; Development; Endothelial Cells; Endothelium; Funding; Genetic; Graft Rejection; Histologic; Host Defense; Human; Immunology; In Vitro; Inflammasome; Inflammation; Inflammatory; Intracranial Hemorrhages; Lesion; Lewy Body Disease; Link; Mediating; Modeling; Mus; Nerve Degeneration; Neurocognitive Deficit; Organ Transplantation; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Permeability; Pharmacology; Plasma Proteins; Play; Predictive Value; Protocols documentation; Role; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Solid; Stains; Structure; System; Testing; Therapeutic; Transplantation; Vascular Diseases; Work; base; brain endothelial cell; cerebrovascular; clinically relevant; disease diagnosis; in vitro Model; in vivo; in vivo Model; insight; macrophage; mouse model; neuron loss; novel; novel strategies; prevent; programs; recruit; translational approach

PROJECT SUMMARY Cerebral amyloid angiopathy (CAA) is an untreatable vasculopathic condition affecting a vast majority of patients with Alzheimer's disease (AD). In CAA, fibrils of Aβ(1-40) deposit in cerebral vessels and promote the development of stenotic lesions, intracranial hemorrhages, and perivascular inflammation. These CAA- associated vascular pathologies show strong linear correlations with the severity of AD, and are thus believed to promote neurodegeneration and contribute to AD dementia. How CAA develops is poorly understood and defining mechanism(s) related to its pathogenesis will define new vascular-based strategies for treating AD. Complement (C') are a conserved system of plasma proteins involved in host defense. Upon activation, C' proteins self-assemble into heterodimeric structures called membrane attack complexes (MAC) that insert as transmembranous pores into target cell membranes. MAC colocalize with Aβ(1-40) deposits in CAA- affected vessels showing evidence of EC activation, and inhibition of complement protein C5, which prevents MAC assembly, blocks progression of AD in a murine mouse model with CAA. In solid organ transplantation, we identified ZFYVE21 as a novel MAC-induced Rab5 effector that activated non-canonical NF-κB, NLRP3 inflammasomes, and canonical NF-κB to mediate endothelial cell (EC) activation and development of vasculopathic lesions. As C' activation, EC activation, and similar forms of vasculopathy are observed in CAA, we explored whether ZFYVE21 signaling may play a role in the development of this condition. We thus embarked on studies defining a role for ZFYVE21 signaling in CAA based on the hypothesis Aβ fibrils activate C' on cerebrovascular ECs to induce ZFYVE21-mediated EC activation to promote CAA vasculopathy and CAA-related neurodegeneration in AD. AD biopsies showed strong staining for MAC, ZFYVE21, and its downstream pathways in Aβ-laden microvessels affected by CAA. To develop mechanism(s) to explain these findings, we optimized an in vitro model of Aβ-induced C' activation that was sufficiently robust to confirm ZFYVE21-mediated signaling in human cerebrovascular endothelial cells (HBMECs). We developed new in vitro and in vivo model systems to examine the functional significance of ZFYVE21 signaling with regards to EC activation, barrier permeability, and macrophage recruitment. In 3 unified aims, we will extend findings from our original proposal to investigate ZFYVE21-mediated mechanisms of EC activation in CAA. Our aims will form the basis for a long-term program invested in studying how C' mediates vascular pathologies to further neurodegeneration in AD.

项目摘要 脑淀粉样血管病（CAA）是一种无法治疗的血管病变，影响绝大多数人， 阿尔茨海默病（AD）患者。在CAA中，Aβ（1-40）纤维存款在脑血管中，并促进 狭窄病变、颅内血肿和血管周围炎症的发展。这些CAA- 相关的血管病理显示出与AD严重程度的强线性相关性， 促进神经退化并导致AD痴呆。CAA是如何发展的，人们知之甚少， 确定与其发病机制相关的机制将确定用于治疗AD的新的基于血管的策略。 补体（C '）是参与宿主防御的血浆蛋白的保守系统。一旦激活， C'蛋白自组装成异二聚体结构，称为膜攻击复合物（MAC）， 作为进入靶细胞膜的跨膜孔。MAC与CAA中Aβ（1-40）共定位。 受影响的血管显示EC激活的证据，并抑制补体蛋白C5，这阻止了 MAC组装体阻断了CAA鼠模型中AD的进展。在实体器官移植中， 我们将ZFYVE 21鉴定为一种新的MAC诱导的Rab 5效应物，其激活非经典NF-κB，NLRP 3 炎症小体和经典NF-κB介导内皮细胞（EC）活化和 血管病变由于在CAA中观察到C'活化、EC活化和类似形式的血管病变， 我们探索了ZFYVE 21信号传导是否在这种情况的发展中起作用。 因此，我们开始了基于以下假设定义ZFYVE 21信号传导在CAA中的作用的研究： Aβ纤维激活脑血管内皮细胞C'端诱导ZFYVE 21介导的内皮细胞激活促进CAA 血管病变和CAA相关的神经变性。AD活检显示MAC强染色， ZFYVE 21及其下游通路在CAA影响的载Aβ微血管中的作用。制定机制 为了解释这些发现，我们优化了一个足够稳健的Aβ诱导C'激活的体外模型 以证实人脑血管内皮细胞（HBMEC）中ZFYVE 21介导的信号传导。我们开发 新的体外和体内模型系统，以检查ZFYVE 21信号传导的功能意义， 关于EC激活、屏障渗透性和巨噬细胞募集。在三个统一的目标中，我们将扩展 我们最初提出的研究CAA中ZFYVE 21介导的EC激活机制的研究结果。我们 这些目标将成为一项长期计划的基础，该计划投资于研究C'如何介导血管病变， AD中的进一步神经变性。