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

项目摘要/摘要 阿尔茨海默病(AD)、原发性年龄相关脑病(部分)和慢性创伤性脑病(CTE) 所有这些都是由神经元内神经原纤维缠结(NFT)形成所定义的紧张性病变，主要由 3R/4R阳性的磷酸化tau(p-tau)。它们在组织病理学上有许多不同之处。 然而，失调症。而AD的神经病理诊断需要β-淀粉样斑块的存在 沉积除了NFT的存在外，PART和CTE还代表β-淀粉样蛋白非依赖性自发性病变。 这是一个关键的区别，因为β-淀粉样斑块的存在被认为在AD的致病性中起关键作用。 我们之前的研究已经证明，临床确诊的痴呆症患者和 经神经病理证实的AD病理显示与淀粉样蛋白相关的蛋白质水平升高 与认知正常的受试者相比，与他们的NFT相关的加工和炎症 病理水平，提示β-淀粉样蛋白可能在认知状态中发挥关键作用。此外，还有 NFT在这三种疾病中的分布不同。在海马体中，最严重的p-tau AD的病理通常在内嗅皮层和CA1海马区(在那里也是最接近的 接近β-淀粉样蛋白)，而部分最严重的神经纤维变性最初发生在CA2区 在CTE中，CA2和CA4亚区受影响最大。在公元一年，p-tau NFT 病理按照既定的Braak分期进行，从内嗅觉到新皮质，而部分NFT 病理主要局限于颞叶皮质，而在CTE中，p-tau病理始于 在影响海马体之前，脑沟深处的新皮质呈血管周围分布。在这里，我们 建议研究海马区不同亚区的NFT及其直接微环境 使用NanoStringGeoMx™数字空间技术对经组织病理学证实的AD、部分和CTE患者进行评估 分析(DSP)。我们预测，AD中发现的NFT与部分和CTE中发现的NFT主要在以下方面不同 与β-淀粉样蛋白处理相关的蛋白质，这些变化将反映在认知上的差异 地位，尤其是在广告与零件的比较中。此外，我们预测NFTs的蛋白质组成在 CTE的CA2次区域将更类似于部分CA2次区域的NFT 在CTE的CA4区，反映了β-淀粉样非依赖性神经纤维变性的假说 CA2次区域的人口老龄化在一定程度上更能代表背景老龄化。NFT的微环境也将 与部分AD相比，AD患者可能表现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 评估合并神经退行性疾病(并发路易体痴呆(LBD)和 边缘- 主要年龄相关性TDP-43脑病(晚期)对海马区蛋白质组分的影响 NFTS。这些研究将加强我们目前对NFTs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记物。

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.