Dominantly Inherited Alzheimer Network: Project 3

项目3：新型机制 最近，在理解淀粉样蛋白和tau蛋白变化的轨迹方面取得了重大进展， 晚发性AD（LOAD）和常染色体显性AD（ADAD），明确建立了长期的临床前阶段 在此期间，在症状出现之前就出现了病变。虽然这两种形式的AD共享许多基本的 病理和临床特征，ADAD在机制上是不同的，突变导致过度生产 除了在LOAD中发现的清除受损外，还存在β-淀粉样蛋白的释放。由于这两种形式的AD都很复杂， 由于AD是一种异质性疾病，因此更全面地了解AD对于加快治愈进展是必要的。 现在的挑战仍然是要解开引发和传播疾病的过程，并评估其影响。 作为新的治疗靶点和生物标志物的潜力。特别是，迫切需要更好地 了解其他分子过程跟踪神经退行性变的早期触发因素，如神经- 炎症和突触损伤及其相关的生物标志物，预示着疾病的进展。的 加速阿尔茨海默病药物合作伙伴关系（AMP-AD）联盟已经确定了分子 网络和新的目标生物标志物（包括那些参与神经炎症和突触损伤）， 死后加载脑组织。然而，对APP、PSEN 1和PSEN 2在ADAD中的作用的理解， 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 确定ADAD突变和神经炎症及突触网络对疾病影响的方法 显性遗传阿尔茨海默病网络（DIAN）参与者的进展，反过来， 新的疾病生物标志物。我们假设ADAD中的神经炎症过程，如直接 ADAD脑的分子分析和通过其相关的流体生物标志物在活体中检测， 在疾病自然病程的早期改变，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（通过转录组学和分子生物学分析）， 基于质谱[MS]的蛋白质组学）来定义炎症和突触网络， 在ADAD大脑中失调。与来自突变携带者和同基因对照的网络数据配对 诱导多能干细胞（iPSC）衍生的神经元，星形胶质细胞和小胶质细胞，我们将建立一个系统的 分子相互作用图，以阐明ADAD突变，炎症，突触功能， 和相关的治疗靶点。为了将AD大脑网络信息转化为 具有潜在的临床相关性和实用性，在目标2中，将从DIAN受试者中纵向获得CSF， 通过MS和免疫测定对目标1中揭示的蛋白质进行了询问，沿着几种“新兴”的 神经炎症（YKL-40，sTREM 2，和颗粒蛋白前体）和突触损伤（VILIP-1， 神经颗粒蛋白、SNAP-25和CSF NfL和血浆NfL），其已经显示在LOAD中具有效用。

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.