Insights into Amyloid Pathogenicity Dynamics

摘要 阿尔茨海默病(AD)是一种无法治愈的大脑疾病，目前导致4000多万人衰弱 世界各地的人们。临床上，阿尔茨海默病通常表现为认知能力的缓慢进行性下降 这不可避免地会导致严重的痴呆症。死后经淀粉样β蛋白(A-β)痴呆确诊为AD 含有过度磷酸化的Tau蛋白的多肽、斑块和神经原纤维缠结(NFT)。一个 这种情况证明蛋白质降解所需的正常通路在阿尔茨海默病大脑中受损。它是 普遍认为斑块和缠结在AD中扮演着复杂的角色，Aβ代谢的变化 在tau病理和神经变性的上游引发破坏性的级联反应。然而，我们的 对斑块多样性及其与NFTs的关系的了解仍然有限。值得注意的是， AD中的β和淀粉样斑块最近在美国食品和药物管理局的批准和活动中重新出现。例如， FDA最近批准了aducanumab，通过正电子发射测量，它可以去除淀粉样斑块 体层摄影术。虽然淀粉样斑块在AD中的重要性早已被认识到，但究竟是如何 斑块随着时间的推移而发展，其多样性的程度以及它们与NFTs的关系尚不清楚。 因此，绘制大脑中不同类别淀粉样聚集体的轨迹图是非常重要的。 淀粉样蛋白或同时存在淀粉样蛋白和NFT病理。 项目负责人最近发现了几个重要的早期事件，形成了 β在AD模型脑中的斑块，并开发了几种新的方法来研究这些过程。第一, 我们发现轴突终末蛋白质动态平衡受损是突触的先驱缺陷。 建立阿尔茨海默病早期淀粉样变性的小鼠模型。第二，我们发现定位于轴突的蛋白质 终末通过斑块依赖和独立的机制选择性地阻碍了周转。第三, 结构不同的斑块的形成与不同的Aβ多肽沉积有关。最后，Aβ42 包括初始的核心结构，随后是径向延伸，后来并入Aβ38。严谨地 扩展这些发现，在目标1中，我们将深入表征小鼠模型脑中淀粉样斑块的多样性。 目标2的目标是确定NFT的存在如何影响淀粉样斑块的动力学。这个 拟议的研究将通过描述淀粉样斑块的特征来促进我们对AD的理解 聚集动力学，形成什么结构的Aβ组件，这些低聚物和斑块是如何触发的 导致下游突触功能障碍的机制，以及淀粉样斑块的这些特性是如何 由NFT调制。

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.