Digital Spatial Profiling of Hippocampal Subregions in Alzheimer’s Disease, Primary Age-Related Tauopathy, and Chronic Traumatic Encephalopathy

项目总结/摘要 阿尔茨海默病（AD）、原发性年龄相关性tau蛋白病（PART）和慢性创伤性脑病（CTE） 都代表由神经元内神经元缠结（NFT）形成定义的tau蛋白病， 3R/4 R阳性磷酸化tau蛋白（p-tau）。这些组织之间存在许多组织病理学差异， 然而，混乱。而AD的神经病理诊断需要存在β-淀粉样斑块， 除了NFT的存在之外，PART和CTE还代表β-淀粉样蛋白非依赖性tau蛋白病。 这是一个关键的区别，因为β-淀粉样蛋白斑块的存在被认为是AD致病性的关键， 我们以前的研究表明，临床确定的痴呆症患者， 神经病理学证实的AD病理学具有增加的与淀粉样蛋白相关的蛋白质水平 与认知正常受试者相比， 病理水平，表明β-淀粉样蛋白可能在认知状态中起关键作用。此外， 这三种疾病中NFT的分布不同。在海马体中， AD的病理学通常在内嗅皮层和CA 1海马亚区（在那里它也是最接近的）。 接近β-淀粉样蛋白），而在PART中，最严重的神经退行性变最初发生在CA 2 在CTE中，CA 2和CA 4海马子区域受影响最大。在AD中，p-tau NFT 病理学根据从内嗅到新皮层的Braak分期进行，而在第一部分中，NFT 病理学主要限于颞叶异体皮质，并且在CTE中，p-tau病理学开始于 在海马体本身受到影响之前，脑沟深处的新皮层在血管周围分布。这里我们 我建议研究NFT及其直接的微环境在不同的次区域， 使用Nanostring GeoMx™ Digital Spatial， 分析（DSP）。我们预测，AD中发现的NFT与PART和CTE中的NFT主要在以下方面不同 与β-淀粉样蛋白加工相关的蛋白质，这些变化将反映在认知功能的差异中。 特别是在AD与PART的比较中。此外，我们预测，NFT的蛋白质组成， CTE的CA 2亚区与PART的CA 2亚区中的NFT相比， 在CTE的CA 4亚区，反映了β-淀粉样蛋白非依赖性神经退行性变 CA 2亚区的CA 1和CA 2亚区的CA 2更能代表PART中的背景老化。NFT微环境还将 与PART相比，AD可能显示出更严重的突触丢失。最后，我们将使用这种空间蛋白质组学方法 评估共病神经退行性疾病（并发路易体痴呆（LBD）和 边缘系统， 主要年龄相关性TDP-43脑病（LATE））对海马神经元蛋白质组成的影响 NFT。这些研究将加强我们目前对NFT致病性的理解， 海马体，并可能有助于开发这些疾病的下一代生物标志物。

Project Summary/Abstract Alzheimer disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all represent tauopathies defined by intra-neuronal neurofibrillary tangle (NFT) formation principally composed of 3R/4R-positive phosphorylated-tau (p-tau). There are numerous histopathological differences between these disorders, however. While the neuropathologic diagnosis of AD requires the presence of β-amyloid plaque deposition in addition to the presence of NFTs, PART and CTE represent β-amyloid-independent tauopathies. This is a key difference as the presence of β-amyloid plaques is thought to be crucial in the pathogenicity of AD, and our previous studies have demonstrated that subjects with clinically determined dementia and neuropathologically-confirmed AD pathology have increased levels of proteins associated with amyloid processing and inflammation associated with their NFTs compared to cognitively normal subjects with similar levels of pathology, suggesting that β-amyloid may play a key role in the cognitive status. Furthermore, there is a different distribution of NFTs among these three disorders. In the hippocampus, the most severe p-tau pathology in AD is often in the entorhinal cortex and CA1 hippocampal subregion (where it is also in closest proximity to β-amyloid), while in PART the most severe neurofibrillary degeneration initially occurs in the CA2 subregion, and in CTE the CA2 and CA4 hippocampal subregions are most affected. In AD, the p-tau NFT pathology proceeds according to established Braak stages from entorhinal to neocortex, while in PART the NFT pathology is primarily restricted to the temporal allocortex, and in CTE the p-tau pathology begins in the neocortex at the depths of sulci in a perivascular distribution before affecting the hippocampus itself. Here, we propose to examine the NFTs and their immediate microenvironments in different subregions of the hippocampi of patients with histopathologically-confirmed AD, PART, and CTE using Nanostring GeoMx™ Digital Spatial Profiling (DSP). We predict that the NFTs found in AD will differ from the those in PART and CTE primarily in proteins related to β-amyloid processing and that these changes will be reflected in differences in cognitive status, especially in the AD to PART comparison. In addition, we predict that the protein composition of NFTs in the CA2 subregion of CTE will be more similar to the NFTs in the CA2 subregion of PART than they are to those in the CA4 subregion of CTE, reflecting the hypothesis that β-amyloid-independent neurofibrillary degeneration of the CA2 subregion is more representative of background aging in PART. The NFT microenvironment will also likely show more severe synaptic loss in AD compared to PART. Finally, we will use this spatial proteomic method to assess the impact of comorbid neurodegenerative conditions (concurrent Lewy body dementia (LBD) and limbic- predominant age-related TDP-43 encephalopathy (LATE)) on the protein composition of hippocampal NFTs. These studies will enhance our current understanding of the pathogenicity of NFTs at the level of the hippocampus and will potentially aid in the development of the next generation of biomarkers for these disorders.