Understanding Amyloid Pathology - Multiomic Activity Imaging of Plaque Formation Dynamics (AmyMAP)

了解淀粉样蛋白病理学 - 斑块形成​​动力学的多组学活性成像 (AmyMAP)

• 批准号: 10516489
• 负责人: Jorg Hanrieder
• 金额: $ 57.97万
• 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: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516489
• 关键词: 3-Dimensional; Address; Aducanumab; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Autopsy; Axon; Brain; Brain Diseases; Characteristics; Chronology; Clinical; Communication; Communities; Complex; Confocal Microscopy; Data Set; Defect; Dementia; Dendrites; Dendritic Spines; Deposition; Disease Progression; Dissection; Electrophysiology (science); Endocytosis; Event; Excision; Extracellular Space; Fluorescent Dyes; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Image; Impaired cognition; Impairment; Individual; Kinetics; Knock-in Mouse; Knowledge; Label; Lasers; Link; Lipids; Maps; Mass Spectrum Analysis; Measures; Metabolism; Methods; Molecular; Molecular Profiling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurosciences Research; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Persons; Play; Positron-Emission Tomography; Presynaptic Terminals; Probability; Process; Protein Analysis; Protein Dynamics; Proteins; Proteomics; Radial; Recycling; Research; Resolution; Risk Factors; Rodent; Role; Senile Plaques; Stable Isotope Labeling; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; TREM2 gene; Testing; Time; TimeLine; United States; amyloid pathology; base; brain tissue; cognitive performance; conformational conversion; density; genetic risk factor; hyperphosphorylated tau; image guided; mass spectrometric imaging; molecular phenotype; mouse model; multiple omics; neuronal circuitry; neurotoxicity; novel strategies; prevent; protein aggregation; protein degradation; proteostasis; public health relevance; response; tau Proteins; tau aggregation; tissue fixing; vesicular release

ABSTRACT Alzheimer's disease (AD) is an incurable brain disorder that currently debilitates more than five million people in the United States alone. Clinically, AD typically presents as a slow and progressive decline in cognitive performance that inevitably culminates in severe dementia. Currently AD can only be positively confirmed postmortem by dementia with amyloid beta (Aβ) peptides plaques and neurofibrillary tangles containing the hyper-phosphorylated Tau protein. It is generally accepted that plaques and tangles play important and complex roles in AD. The prevailing model of AD pathogenesis has been that changes in Aβ metabolism precipitate a damaging cascade upstream of tau pathology and eventual neurodegeneration. However, there is a lot about these enigmatic pathological marks that we do not understand. 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 the amyloid plaques in AD have long been recognized, exactly how plaques develop over time, the extent of their diversity, and their relation to toxic or homeostatic response of the surrounding neuronal circuits remains unclear. Therefore, it is of great importance to map the trajectory of distinct classes of amyloid aggregates during the early stages of A pathology. We have recently discovered several important and early events in the formation of A 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 amyloid model mice. Second, we found that the synaptic vesicle release and recycling machinery has 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 obtain a dynamic map of amyloid plaque pathology in mouse model brains during aging. The goal of Aim 2 is to determine how the AD risk factor Trem2 influences A, lipid, and protein dynamics at amyloid plaques. In Aim 3, we will integrate the multi-omic amyloid maps with measures of altered synaptic communication and neurotoxicity. Finally, in Aim 4, we apply the knowledge gained in a practical manner with 3D mapping for the neuroscience research community. The proposed research will advance our understanding of AD by determining when Aβ is aggregating in the extracellular space, what structural Aβ assemblies are formed, and how these oligomers and plaques trigger mechanisms leading to downstream synaptic dysfunction.

摘要 阿尔茨海默氏病（AD）是一种无法治愈的脑部疾病，目前使500多万人衰弱 仅在美国。在临床上，AD通常表现为慢性和进行性下降， 最终导致严重的痴呆症目前AD只能是正面的 尸检证实为痴呆伴淀粉样β（Aβ）肽斑块和神经系统缠结 含有高度磷酸化的Tau蛋白。人们普遍认为，斑块和缠结发挥作用， 在AD中扮演着重要而复杂的角色。AD发病机制的流行模型是Aβ的变化， 代谢在tau病理学上游沉淀破坏性级联反应并最终导致神经变性。 然而，有很多关于这些神秘的病理标记，我们不了解。的相关性 AD中的Aβ和淀粉样蛋白斑块最近在FDA的批准和活动中有所复苏。比如说 FDA最近批准了aducanumab，通过正电子发射测量， 断层扫描虽然淀粉样蛋白斑块在AD中的重要性早已被认识到， 斑块随着时间的推移而发展，其多样性的程度，以及它们与毒性或稳态反应的关系， 周围的神经回路仍不清楚因此，绘制出 不同类别的淀粉样蛋白聚集体在阿尔茨海默病的早期阶段。 我们最近发现了AD中A β斑块形成的几个重要和早期事件 他们建立了大脑模型，并开发了几种新的方法来研究这些过程。首先，我们发现， 轴突末端中受损的蛋白质稳态代表淀粉样蛋白模型小鼠中的开创性突触缺陷。 其次，我们发现突触囊泡的释放和再循环机制选择性地阻碍了周转 通过斑块依赖性和非依赖性机制。第三，结构上不同的斑块的形成是 与差异性Aβ肽沉积有关。最后，Aβ42包含初始核心结构， 放射状生长和随后的Aβ38掺入。为了严格扩展这些发现，在目标1中，我们将获得 衰老过程中小鼠模型脑中淀粉样斑块病理学的动态图。目标2的目标是 确定AD风险因子Trem2如何影响淀粉样斑块中的A β、脂质和蛋白质动力学。在Aim中 3，我们将整合多组学淀粉样蛋白图谱与改变的突触通讯的措施， 神经毒性最后，在目标4中，我们以实际的方式将所获得的知识与3D映射应用于 神经科学研究社区拟议的研究将通过以下方式促进我们对AD的理解 确定Aβ何时在细胞外空间聚集，形成什么样的结构Aβ组装体，以及 这些寡聚体和斑块如何触发导致下游突触功能障碍的机制。