APOE as a modifier of prion-like spread in dementia

APOE 作为痴呆症中朊病毒样传播的修饰剂

• 批准号: 9531688
• 负责人: DAVID R BORCHELT
• 金额: $ 261.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9531688
• 关键词: Acceleration; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloidosis; Animal Model; Animals; Apolipoprotein E; Attenuated; Automobile Driving; Biological Sciences; Brain; Brain Diseases; Characteristics; Data; Dementia; Deposition; Genes; Genotype; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Injections; Laboratories; Left; Mediating; Modeling; Morphology; Mus; Nerve Degeneration; Newborn Infant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Phosphorylation; Process; Protein Isoforms; Reporting; Risk; Secondary to; Seeds; Severities; Standardization; Tauopathies; Testing; Transgenes; Transgenic Mice; Variant; abeta deposition; amyloid peptide; conformer; genetic risk factor; inflammatory marker; misfolded protein; mouse model; multidisciplinary; mutant; overexpression; preclinical study; prion-like; protein B; protein aggregate; tau Proteins; tau phosphorylation

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.

APOE作为痴呆症中朊病毒样扩散的修饰剂 翻译后摘要：这个多学科项目的总体目标是测试的假设，相对于APOE 2 或APOE3、APOE4促进错误折叠的A β和tau的播种和扩散。APOE4等位基因的遗传 会显著增加患阿尔茨海默病（AD）的风险。大多数研究表明， APOE基因型调节AD风险的机制是通过影响A β肽的沉积。 然而，有研究表明，APOE也可能直接调节磷酸化和错误折叠， 关于Tau有些令人惊讶的是，虽然第一次描述A β在小鼠中的播种报告超过200次，但在2000年， 10年前和各种人类APOE模型已经存在多年，一直没有 研究APOE基因型如何调节错误折叠A β的播种或扩散。同样，没有 研究APOE基因型如何影响错折叠tau蛋白的传播。我们现在提出三个目标， 对人类APOE的不同亚型如何影响朊病毒样蛋白进行全面和系统的评估。 错误折叠的A β和tau的播种和扩散。我们研究的一个组成部分也将评估不同的APOE是否 同种型可以与这些聚集蛋白相互作用以产生错误折叠的A β或tau的不同菌株。要求1 将确定APOE2、APOE3和APOE4支持A β病理接种的相对能力， A β聚集体在脑内的扩散，以及APOE同种型是否调节A β聚集体的应变特征。 接种的A β聚集体。目的2将确定APOE基因型是否影响CNS tau的传播 病理学，以及观察到的任何传播影响是否可能是由于不同菌株的出现 错误折叠的tau蛋白目的3将研究APOE亚型是否可以差异调节A β诱导的 Tau的错误折叠。总的来说，这些研究将产生一个独特的动物模型库，并提供 第一次评估不同的人APOE同种型是否可能通过以下方式影响AD的发病机制： 调节朊病毒样播种或错误折叠的A β和tau的扩散。