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

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500多万人虚弱 仅在美国的人。在临床上，AD通常表现为缓慢和渐进性的下降 不可避免地导致严重痴呆症的认知表现。目前AD只能为正 死后确认为痴呆症的淀粉样β蛋白(Aβ)多肽斑块和神经原纤维缠结 含有高度磷酸化的Tau蛋白。人们普遍认为，斑块和缠结 AD中重要而复杂的角色。AD发病机制的主要模式是Aβ的改变 新陈代谢导致tau病理上游的破坏性级联反应，最终导致神经变性。 然而，关于这些神秘的病理标志，我们还有很多不了解的地方。的关联性 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。尽管淀粉样斑块在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，以及它们与毒性或内环境平衡反应的关系 周围的神经元回路仍不清楚。因此，绘制其轨迹图具有重要意义。 在A病理的早期阶段不同类型的淀粉样聚集体。 我们最近在AD的斑块的形成中发现了几个重要的早期事件 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， 轴突终末蛋白动态平衡受损是淀粉样蛋白模型小鼠突触的先驱缺陷。 其次，我们发现突触小泡的释放和回收机制选择性地阻碍了细胞的周转。 通过斑块依赖和独立的机制。第三，结构上不同的斑块的形成是 与不同的Aβ多肽沉积有关。最后，β42包括初始核心结构，其后是 放射状生长和后来并入Aβ38。为了严格扩展这些发现，在目标1中，我们将获得一个 衰老过程中小鼠脑内淀粉样斑块病理的动态图谱。目标2的目标是 确定AD风险因素TREM2如何影响淀粉样斑块的A、脂质和蛋白质动力学。在AIM 3，我们将整合多组淀粉样蛋白图谱与突触通讯改变和 神经毒性。最后，在目标4中，我们将以实用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β何时在细胞外空间聚集，形成什么结构的Aβ组件，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。

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.