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 阿尔茨海默氏病（AD）是痴呆症最常见的形式，导致显着降低 受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的沉积已记录在 AD中的外围器官，我们提供了证据表明心脏是受影响的器官之一。我们 其他人也表明，完成系统在 通过标记和打击来创建和维持非炎症性血管内环境 用C1Q，MBL，C3B和C4B循环外国或绝对折叠的宿主蛋白。重要的是，免费 Aβ42结合4个Cr1中的3个（补体受体1）配体C1Q，C3B和C4B。在 完成Aβ42的存在在循环RBC上结合CR1。 RBC独有的表达 CR1的水平通常确定，个体表达90份CR1/RBC副本 （l/low），500 CR1副本（HL/中级）或1200 CR1副本（H/High Expressers）。最近， 使用GWAS数据的几份报告，将CR1多态性连接到了迟到AD的风险增加， 借给RBC在AD发病机理中的作用。在AD患者中 最近，基于Aβ水平从肝脏，心脏和周围的转移提出了血液Aβ。 基于这些观察，该应用程序的总体假设是 确定的循环RBC上的CR1水平至关重要：a）结合并安全去除循环Aβ b）防止无细胞的Aβ转移到RBC细胞质中，并通过外泌体传递到 损害外周组织，例如心脏，导致心力衰竭，进而令人担忧的AD。我们 将通过以下方式检验和验证这一假设 电动汽车，RBC中的Aβ和血液中的自由。 b）定义自由与电动汽车的功能后果 Aβ使用Lox-Cre小鼠模型在大脑和心脏之间穿梭，c）验证 使用AD患者的组织样品AD发病机理中的RBC和电动汽车 这项研究的结果支持免费使用的未来和rbc结合的Aβ42作为生物标志物 疾病进展和治疗进展的水库。