Insights into Amyloid Pathogenicity Dynamics

淀粉样蛋白致病动力学的见解

• 批准号: 10590478
• 负责人: Jorg Hanrieder
• 金额: $ 23.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590478
• 关键词: 3xTg-AD mouse; Aducanumab; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Autopsy; Brain; Brain Diseases; Chronology; Classification; Clinical; Complex; Defect; Dementia; Deposition; Dissection; Endocytosis; Event; Extracellular Space; Functional disorder; Goals; Impaired cognition; Impairment; Individual; Kinetics; Knock-in Mouse; Label; Lasers; Link; Maps; Mass Spectrum Analysis; Measures; Metabolism; Methods; Microglia; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peptides; Persons; Phosphorylation; Play; Positron-Emission Tomography; Presynaptic Terminals; Process; Property; Protein Analysis; Proteins; Proteomics; Radial; Research; Resolution; Rodent; Role; Senile Plaques; Stable Isotope Labeling; Structure; Synapses; Synaptic Vesicles; Testing; Thinness; Time; amyloid pathology; cognitive performance; human old age (65+); hyperphosphorylated tau; image guided; insight; mass spectrometric imaging; molecular phenotype; mouse model; neurofibrillary tangle formation; novel strategies; pre-clinical; protein aggregation; protein degradation; proteostasis; public health relevance; tau Proteins; tau-1; timeline

ABSTRACT Alzheimer’s disease (AD) is an incurable brain disorder that currently debilitates more than 40 million people worldwide. Clinically, AD typically presents as a slow and progressive decline in cognitive performance that inevitably culminates in severe dementia. AD is confirmed postmortem by dementia with amyloid beta (Aβ) peptides plaques and neurofibrillary tangles (NFTs) containing the hyper-phosphorylated Tau protein. A situation which proves that the normal pathways required for protein degradation are impaired in AD brain. It is generally accepted that plaques and tangles play complex roles in AD and that changes in Aβ metabolism precipitate a damaging cascade upstream of tau pathology and neurodegeneration. However, our understanding of plaque diversity and how this relates to NFTs has remained limited. Notably, the relevance of Aβ and amyloid plaques in AD has seen a recent resurgence in FDA approvals and activities. For example, the FDA recently approved aducanumab that can remove amyloid plaques as measured by positron-emission tomography. Although the importance of amyloid plaques in AD have long been recognized, exactly how plaques develop over time, the extent of their diversity, and their relationship to NFTs is not well understood. Therefore, it is of great importance to map the trajectory of distinct classes of amyloid aggregates in brains with amyloid or both amyloid and NFT pathology. The project leaders recently discovered several important and early events in the formation of Aβ plaques in AD model brains and have developed several new approaches to study these processes. First, we discovered that impaired protein homeostasis in axon terminals represents a pioneering synaptic defect in mice modeling the early stage of amyloid pathology in AD. Second, we found that proteins localizing to axon terminals have selectively hampered turnover through plaque dependent and independent mechanisms. Third, formation of structurally distinct plaques are associated with differential Aβ peptide deposition. Finally, Aβ42 comprises the initial core structure followed by radial outgrowth and later incorporation of Aβ38. To rigorously extend these findings, in Aim 1 we will deeply characterize amyloid plaque diversity in mouse model brains. The goal of Aim 2 is to determine how the presence of NFTs influence amyloid plaque dynamics. The proposed research will advance our understanding of AD by characterizing amyloid plaques based on aggregation kinetics, what structural Aβ assemblies are formed, how these oligomers and plaques trigger mechanisms leading to downstream synaptic dysfunction, and how these properties of amyloid plaques are modulated by NFTs.

抽象的 阿尔茨海默氏病（AD）是一种无法治愈的脑疾病，目前衰弱超过4000万 全球人。临床上，广告通常表现为认知表现缓慢而逐渐下降 这不可避免地达到严重痴呆症。 AD通过淀粉样蛋白β（Aβ）证实了痴呆症后尸体证实 肽斑块和含有高磷酸化tau蛋白的神经纤维缠结（NFT）。一个 情况证明蛋白质降解所需的正常途径在AD大脑中受损。这是 普遍认为，斑块和缠结在AD中起复杂的作用，并且Aβ代谢的变化 在tau病理学和神经变性的上游造成破坏性的级联反应。但是，我们的 对斑块多样性以及与NFT的关系的理解仍然有限。值得注意的是，相关性 AD中的Aβ和淀粉样斑块最近在FDA批准和活动中复兴。例如， FDA最近批准了可以通过正电子发射测量的可以去除淀粉样蛋白斑块的aducanumab 层析成像。尽管长期以来已经认识到淀粉样蛋白斑块在广告中的重要性。 斑块随着时间的流逝而发展，其多样性的程度以及其与NFT的关系尚不清楚。 因此，绘制大脑中不同类别的淀粉样蛋白聚集体的轨迹非常重要 淀粉样蛋白或淀粉样蛋白和NFT病理学。 项目负责人最近发现了几个重要的早期事件 广告模型大脑中的Aβ斑块，并开发了几种研究这些过程的新方法。第一的， 我们发现，轴突终端中蛋白质稳态受损，代表着一个先锋的突触缺陷 在AD中建模淀粉样病理早期的小鼠。其次，我们发现蛋白质定位于轴突 末端通过斑块依赖和独立机制有选择地阻碍了营业额。第三， 结构上不同的斑块的形成与差异Aβ肽沉积有关。最后，Aβ42 包括初始核心结构，然后进行径向生长，然后掺入Aβ38。严格 扩展了这些发现，在AIM 1中，我们将深刻地表征小鼠模型大脑中的淀粉样蛋白斑块多样性。 目标2的目的是确定NFT的存在如何影响淀粉样斑块动力学。 拟议的研究将通过表征基于淀粉样蛋白斑块来提高我们对AD的理解。 聚集动力学，形成哪些结构Aβ组件，这些低聚物和斑块如何触发 导致下游突触功能障碍的机制，以及这些淀粉样斑块的特性如何 由NFT调节。