Dominantly Inherited Alzheimer Network: Project 3

项目3：新机制项目摘要/摘要 最近，在了解淀粉样蛋白和tau蛋白的变化轨迹方面取得了重大进展。 晚发性(LOAD)和常染色体显性AD(ADAD)，清楚地建立了一个漫长的临床前阶段 在此期间，先出现病理，再出现症状。虽然这两种形式的AD有许多共同的基础 ADAD的病理和临床特征在机制上是不同的，突变导致生产过剩 除了在LOAD中发现的清除障碍外，还存在β-淀粉样蛋白的损害。由于这两种形式的AD都很复杂， 异质性的，对AD的更全面的了解对于加速治疗进展是必要的。 现在的挑战仍然是揭开引发和传播疾病的过程并评估它们的 有可能成为新的治疗靶点和生物标记物。特别是，迫切需要更好地 了解追踪神经退行性变早期触发因素的其他分子过程，如神经- 炎症和突触损伤及其相关的预示疾病进展的生物标志物。这个 加速阿尔茨海默病药物伙伴关系(AMP-AD)联盟已经确定了分子 网络和新的靶向生物标记物(包括参与神经炎症和突触损伤的那些) 死后脑组织负荷过重。然而，对APP、PSEN1和PSEN2在ADAD中作用的理解 发病机制和下游机制仍然有限。项目3的目标是使用基于系统的 确定ADAD突变以及神经炎性和突触网络对疾病影响的方法 多米尼利遗传性阿尔茨海默病网络(DIAN)参与者的进展，这反过来将识别 新的疾病生物标志物。我们假设ADAD中的神经炎性过程，如DIRECT所定义的 对ADAD脑的分子分析以及通过其相关的流体生物标记物在活体中检测到的ADAD是 在疾病的自然病程早期改变，并影响进行性神经元损伤和认知能力下降。 在目标1中，我们将使用“组学”和系统生物学方法(通过转录组学和 基于质谱仪[MS]的蛋白质组学)来定义炎症和突触网络 ADAD大脑中的调节失调。与来自突变携带者和同基因控制的网络数据配对 诱导多能干细胞(IPSC)来源的神经元、星形胶质细胞和小胶质细胞，我们将创造一个系统的 分子相互作用图阐明ADAD突变、炎症、突触功能、 以及相关的治疗靶点。为了将AD大脑网络信息转换为 具有潜在的临床相关性和实用性，在目标2中，纵向从DIAN参与者那里获得的CSF将是 通过MS和免疫分析对AIM 1中显示的蛋白质进行询问，以及几个“新出现的” 神经炎症(YKL-40、sTREM2和原颗粒蛋白)和突触损伤的生物标记物(VILIP-1、 神经颗粒素、SNAP-25、脑脊液NFL和血浆NFL)，这些已经被证明在负荷中有用。

Project 3: Novel Mechanisms PROJECT SUMMARY/ABSTRACT Recently, significant progress has been made in understanding the trajectory of amyloid and tau changes in both late-onset (LOAD) and autosomal-dominant AD (ADAD), clearly establishing a long preclinical stage during which pathologies develop prior to symptoms. While these two forms of AD share many fundamental pathological and clinical features, ADAD is mechanistically distinct, with mutations resulting in overproduction of β-amyloid in addition to impaired clearance as is found in LOAD. Since both forms of AD are complex and heterogeneous, a more complete understanding of AD is necessary to accelerate progress towards a cure. Challenges now remain to unravel the processes that initiate and promulgate disease and to assess their potential as novel therapeutic targets and biomarkers. In particular, there is an urgent need to better understand other molecular processes tracking early triggers of neurodegeneration, such as neuro- inflammation and synaptic injury and their associated biomarkers that herald disease progression. The Accelerating Medicines Partnership for Alzheimer’s disease (AMP-AD) consortium has identified molecular networks and novel target biomarkers (including those involved in neurinflammation and synaptic injury) in post-mortem LOAD brain tissue. However, the understanding of the role of APP, PSEN1 and PSEN2 in ADAD pathogenesis and downstream mechanisms remains limited. The goal of Project 3 is to use systems-based approaches to define the impact of ADAD mutations and neuroinflammatory and synaptic networks on disease progression in participants in the Dominantly Inherited Alzheimer network (DIAN), which will, in turn, identify novel disease biomarkers. We hypothesize that neuroinflammatory processes in ADAD, as defined by direct molecular analysis of ADAD brain and detected in living individuals by their associated fluid biomarkers, are altered early in the natural course of disease and impact progressive neuronal injury and cognitive decline. In Aim 1, we will use “-omics” and systems biology approaches (with molecular profiling via transcriptomics and mass spectrometry [MS]-based proteomics) to define the inflammatory and synaptic networks that are dysregulated in ADAD brains. Paired with network data derived from mutation carriers and isogenic control induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, and microglia, we will create a systematic molecular interaction map to elucidate connections between ADAD mutations, inflammation, synaptic function, and associated therapeutic targets. In order to translate AD brain network information into applications that have potential clinical relevance and utility, in Aim 2, CSF obtained longitudinally from DIAN participants will be interrogated by MS and immunoassays for proteins revealed in Aim 1, along with several “emerging” biomarkers of neuroinflammation (YKL-40, sTREM2, and progranulin) and synaptic injury (VILIP-1, neurogranin, SNAP-25, and CSF NfL and plasma NfL) which have already shown to have utility in LOAD.