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.

摘要 阿尔茨海默病（AD）是最常见的痴呆形式，其导致阿尔茨海默病（AD）的显著减少。 影响患者的生活质量。在AD患者的大脑中，β-淀粉样蛋白（Aβ）被确定为 淀粉样斑块的主要成分。最近，Aβ沉积物已被记录在 我们提供了证据表明心脏是受影响的器官之一。我们 和其他研究也表明，补体系统在免疫系统中具有关键的、非冗余的作用。 通过标记和调理作用产生并维持非炎症性血管内环境 具有C1 q、MBL、C3 b和C4 b的循环外来或异常折叠的宿主蛋白。重要的是，免费 Aβ42结合4种CR 1（补体受体1）配体中的3种，即C1 q、C3 b和C4 b。在 补体Aβ42的存在结合循环RBC上的CR 1。红细胞特有的表达 CR 1水平由基因决定，个体表达90个CR 1/RBC拷贝 （L/低），500个CR 1拷贝（HL/中间）或1200个CR 1拷贝（H/高表达者）。最近， 几份使用GWAS数据的报告将CR 1多态性与迟发性AD的风险增加联系起来， 从而证实红细胞在AD发病机制中的作用。在AD患者中， 最近，基于Aβ水平从肝脏向脑、心脏和外周的转移，提出了血液Aβ。 基于这些观察结果，本申请的总体假设是， 循环RBC上确定的CR 1水平在以下方面至关重要：a）结合并安全清除循环Aβ 和B）防止无细胞Aβ易位至RBC胞质溶胶并通过外泌体递送至 损伤外周组织如心脏，导致心力衰竭，进而恶化AD。我们 将通过以下方式测试和验证这一假设：A）调查RBC-CR 1水平在分布中的作用 在EV、RBC和血液中游离的Aβ。B）定义游离与结合EV的功能后果 使用lox-cre小鼠模型，Aβ在脑和心脏之间穿梭，以及C）验证A β的作用。 使用来自AD患者的组织样品的AD发病机制中的RBC和EV 本研究结果支持游离和红细胞结合Aβ42作为生物标志物的应用前景 储库以分期疾病进展和治疗进展。