APOE as a modifier of prion-like spread in dementia

标题：载脂蛋白E作为痴呆症中蛋白酪氨酸类扩散的修饰物 摘要：这个多学科项目的总体目标是检验与载脂蛋白2相关的假设 或APOE3，APOE4促进错误折叠的Aβ和tau的播种和扩散。载脂蛋白4等位基因的遗传 极大地增加了患阿尔茨海默病(AD)的风险。大多数研究表明，主要的 载脂蛋白E基因调整AD风险的机制是通过影响Aβ多肽的沉积来实现的。 然而，有研究表明，载脂蛋白E也可能直接调节磷酸化和错误折叠 陶氏家族的。有些令人惊讶的是，尽管关于β在小鼠身上播种的第一次描述超过了 10年前，各种人类APOE模型已经出现多年，还没有 载脂蛋白E基因如何调节错误折叠的Aβ的播种或传播的研究。同样，也没有 研究载脂蛋白E基因如何影响错误折叠的tau的传播。我们现在提出三个目标： 对人类载脂蛋白E的不同亚型如何影响类普里子进行彻底和系统的评估 错误折叠的Aβ和Tau的播种和传播。我们研究的一个组成部分还将询问不同的APOE 异构体可能与这些聚集的蛋白质相互作用，产生不同的错误折叠的Aβ或tau菌株。目标1 将决定载脂蛋白2、载脂蛋白3和载脂蛋白4支持Aβ病理播种的相对能力， Aβ在脑内聚集的传播，以及APOE亚型是否调节 种子Aβ聚集在一起。目标2将确定载脂蛋白E基因是否影响中枢神经系统tau的传播 病理，以及观察到的传播影响是否潜在地归因于不同菌株的出现 折错了的牛排。目标3将研究载脂蛋白E亚型是否可以差异地调制β诱导的A Tau的错误折叠。总的来说，这些研究将产生一套独特的动物模型，并提供 首次评估不同人类载脂蛋白E亚型是否可能通过以下方式影响AD的发病 调节错误折叠的Aβ和tau的普里子样播种或扩散。

Title: APOE as a modifier of prion-like spread in dementia Abstract: The overall objective of this multidisciplinary project is to test the hypothesis that relative to APOE2 or APOE3, APOE4 facilitates the seeding and spread of misfolded Aβ and tau. Inheritance of an APOE4 allele increases the risk of developing Alzheimer's disease (AD) dramatically. Most studies suggest that the primary mechanism by which APOE genotype modulates the risk for AD is by influencing the deposition of Aβ peptide. However, there are studies that suggest APOE may also directly modulate the phosphorylation and misfolding of tau. Somewhat surprisingly, although the first descriptions of Aβ seeding in mice were reported more than 10 years ago and various human APOE models have been available for many years, there have been no studies of how APOE genotype may modulate seeding or spread of misfolded Aβ. Similarly, there has been no study of how APOE genotype may influence the spread of misfolded tau. We now propose three Aims to conduct a thorough and systematic assessment of how different isoforms of human APOE impact the prion-like seeding and spread of misfolded Aβ and tau. A component of our study will also asess whether different APOE isoforms may interact with these aggregating proteins to produce distinct strains of misfolded Aβ or tau. Aim 1 will determine the relative ability of APOE2, APOE3 and APOE4 to support the seeding of Aβ pathology, the spread of Aβ aggregates within the brain, and whether APOE isoforms modulates the strain characteristics of the seeded Aβ aggregates. Aim 2 will determine whether APOE genotype influences the spread of CNS tau pathology, and whether any observed influence in spread is potentially due to the emergence of distinct strains of misfolded tau. Aim 3 will examine whether APOE isoforms may differentially modulate Aβ-induced misfolding of tau. Collectively, these studies will produce a unique repertoire of animal models and provide the first assessment of whether different human APOE isoforms may be influencing that pathogenesis of AD by modulating the prion-like seeding or spread of misfolded Aβ and tau.