Red Blood Cells shuttle beta amyloid between brain and heart: implications for the pathogenesis and the progression of Alzheimer's and Cardiomyopathy

红细胞在大脑和心脏之间穿梭β淀粉样蛋白：对阿尔茨海默病和心肌病的发病机制和进展的影响

• 批准号: 10319189
• 负责人: IONITA Calin GHIRAN
• 金额: $ 49.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319189
• 关键词: Adsorption; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Binding; Biological Assay; Biological Markers; Blood; Brain; Brain region; Buffers; Cardiac Myocytes; Cardiomyopathies; Cell Communication; Cell membrane; Cell surface; Cells; Complement; Complement 1q; Complement 3b; Complement 4b; Complement Activation; Complement Receptor; Cytosol; Data; Defect; Dementia; Deposition; Disease; Disease Progression; Distal; Drug or chemical Tissue Distribution; Ensure; Environment; Erythrocytes; Fluorescence; Future; Gender; Genetic Polymorphism; Heart; Heart failure; Human; Immobilization; In Vitro; Individual; Kupffer Cells; Late Onset Alzheimer Disease; Left; Ligands; Light; Link; Liver; Mediating; Microglia; Mus; Myocardial tissue; Neuraxis; Neuronal Dysfunction; Neurons; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Plasma; Process; Proteins; Proxy; Quality of life; Reporting; Risk; Role; Senile Plaques; Structure; System; Testing; Therapeutic; Tissue Sample; Tissues; Validation; base; complement system; exosome; extracellular vesicles; genome wide association study; heart function; human tissue; immune clearance; in vivo; mouse model; neuron loss; particle; prevent

Abstract Alzheimer disease (AD) is the most frequent form of dementia causing a significant reduction of quality of life of affected patients. In the brains of AD patients, β-amyloid (Aβ) was identified as the main component of the amyloid plaques. Recently, deposits of Aβ have been documented in peripheral organs in AD and we provided evidence that the heart is one of the affected organs. We and others, have also shown that the complement system has a critical, non-redundant roles in creating and maintaining a non-inflammatory intravascular environment by tagging and opsonizing circulating foreign or abnormally folded host proteins with C1q, MBL, C3b and C4b. Importantly, free Aβ42 binds 3 out of 4 CR1 (complement receptor 1) ligands namely C1q, C3b and C4b. In the presence of complement Aβ42, binds CR1 on circulating RBCs. Unique to RBCs, the expression levels of CR1 are genetically determined, with individuals expressing either 90 copies of CR1/RBC (L/low), 500 CR1 copies (HL/intermediate) or 1200 CR1 copies (H/high expressers). Recently, several reports using GWAS data, linked CR1 polymorphisms to an increased risk of late-onset AD, lending credence to the role for RBCs in AD pathogenesis. In AD patients an abnormal clearance in blood Aβ was recently suggested based on a shift in Aβ levels from liver to brain, heart and periphery. Based on these observations, the overall hypothesis of this application is that the genetically determined CR1 levels on circulating RBCs are critical in: a) binding and safely remove circulating Aβ and b) preventing the cell-free Aβ to translocate to the RBC cytosol and be delivered via exosomes to damage peripheral tissues such as the heart, leading to heart failure and, in turn, worsening AD. We will test and validate this hypothesis by: A) Investigating the role of RBC-CR1 levels in the distribution of Aβ in EVs, RBCs and free in blood. B) Defining the functional consequences of free vs. EVs bound Aβ shuttling between brain and heart using a lox-cre mouse model, and C) Validating the role of RBCs and EVs in AD pathogenesis using tissues samples from AD patients The results of this study support the future of use free and RBC-bound Aβ42 as biomarker reservoirs to stage disease progression and therapeutic progresses.

抽象的 阿尔茨海默病 (AD) 是最常见的痴呆症，可导致痴呆症显着减少 在 AD 患者的大脑中，β-淀粉样蛋白 (Aβ) 被确定为影响患者生活质量的因素。 淀粉样斑块的主要成分最近已被记录在 Aβ 沉积物中。 AD 的外周器官，我们提供的证据表明心脏是受影响的器官之一。 等人还表明，补体系统在 通过标记和调理来创建和维持非炎症性血管内环境 循环外源或异常折叠的宿主蛋白，其中包含 C1q、MBL、C3b 和 C4b 重要的是，游离的。 Aβ42 结合 4 个 CR1（补体受体 1）配体中的 3 个，即 C1q、C3b 和 C4b。 补体 Aβ42 的存在与循环红细胞上的 CR1 结合，这是红细胞特有的表达。 CR1 的水平由基因决定，个体表达 90 个 CR1/RBC 拷贝 （L/低）、500 个 CR1 拷贝（HL/中度）或 1200 个 CR1 拷贝（H/高表达者）。 一些使用 GWAS 数据的报告将 CR1 多态性与迟发性 AD 风险增加联系起来， 证实红细胞在 AD 发病机制中的作用。在 AD 患者中，红细胞清除异常。 最近提出血液 Aβ 是基于 Aβ 水平从肝脏到大脑、心脏和外周的变化。 基于这些观察，本申请的总体假设是，遗传 确定循环红细胞上的 CR1 水平对于以下方面至关重要：a) 结合并安全地去除循环 Aβ b) 防止无细胞 Aβ 易位至红细胞胞质并通过外泌体递送至 损害心脏等周围组织，导致心力衰竭，进而导致 AD 恶化。 将通过以下方式测试和验证该假设： A) 调查 RBC-CR1 水平在分布中的作用 B) 定义游离与 EV 结合的功能后果。 使用 lox-cre 小鼠模型进行 Aβ 在大脑和心脏之间穿梭，以及 C) 验证 Aβ 的作用 使用 AD 患者的组织样本研究 RBC 和 EV 在 AD 发病机制中的作用 这项研究的结果支持未来使用游离的和红细胞结合的 Aβ42 作为生物标志物 储存库以分阶段疾病进展和治疗进展。