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

摘要 阿尔茨海默病(AD)是最常见的痴呆症形式，导致 受影响患者的生活质量。在AD患者的大脑中，淀粉样蛋白(β-β，A-A)被鉴定为 淀粉样斑块的主要成分。最近，Aβ的存款被记录在 我们提供了心脏是受影响的器官之一的证据。我们 和其他的，也表明补体系统在 通过标记和优化来创建和维护非炎症性血管内环境 外源或异常折叠的宿主蛋白与C1q、MBL、C3b和C4b循环。重要的是，免费 β42结合4个CR1(补体受体1)配体中的3个，即C1q、C3b和C4b。在 补体Aβ42可与循环中的红细胞结合。RBC所特有的，表达式 CR1的水平是由基因决定的，个体表达90份CR1/RBC (L/低)，500个CR1拷贝(HL/中级)或1200个CR1拷贝(H/高表达)。最近， 几份使用Gwas数据的报告将CR1基因多态与晚发性AD风险增加联系在一起， 证实红细胞在AD发病机制中的作用。在AD患者中， 血液Aβ最近被认为是基于Aβ水平从肝脏到大脑、心脏和外周的变化。 基于这些观察，这一应用的总体假设是，从基因上讲， 已确定的循环β上的CR1水平在以下方面至关重要：a)结合并安全地清除循环A RBC 和b)阻止无细胞的Aβ移位到红细胞胞浆，并通过外体输送到 损害心脏等外周组织，导致心力衰竭，进而加重AD。我们 我将通过：a)调查RBC-CR1水平在分布中的作用来检验和验证这一假设 电动汽车、红细胞和血液中Aβ的含量。B)界定免费电动汽车与受约束电动汽车的功能后果 使用LOX-CRE小鼠模型在大脑和心脏之间穿梭的β，以及C)验证 应用AD患者组织标本检测红细胞和EVS在AD发病中的作用 这项研究的结果支持未来使用自由和红细胞结合的Aβ42作为生物标记物 蓄水池是疾病进展和治疗进展的阶段性阶段。

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.