Dominantly Inherited Alzheimer Network: Project 3

显性遗传阿尔茨海默病网络：项目 3

• 批准号: 10462567
• 负责人: Anne Fagan
• 金额: $ 46.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462567
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Architecture; Astrocytes; Autopsy; Binding; Biological Markers; Biological Process; Brain; Brain Pathology; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Complex; Data; Diagnosis; Disease; Disease Progression; Epigenetic Process; Functional disorder; Genetic; Goals; Human; Immunoassay; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Inflammation; Inflammatory; Information Networks; Inherited; Injury; Lead; Light; Link; Liquid substance; Maps; Mass Spectrum Analysis; Measures; Medicine; Microglia; Molecular; Molecular Analysis; Molecular Profiling; Mutation; Natural History; Nerve Degeneration; Network-based; Neurofibrillary Tangles; Neuronal Injury; Neurons; Observational Study; PGRN gene; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Phenotype; Plasma; Positron-Emission Tomography; Process; Prognostic Marker; Proteins; Proteomics; Role; S-nitro-N-acetylpenicillamine; Sampling; Senile Plaques; Symptoms; Synapses; System; Systems Biology; Therapeutic Trials; Time; Translating; VSNL1 gene; autosomal dominant Alzheimer' s disease; base; brain tissue; candidate marker; cell type; clinically relevant; cohort; diagnostic biomarker; inflammatory marker; interdisciplinary approach; longitudinal analysis; mutation carrier; neurofilament; neurogranin; neuroinflammation; neuropathology; new therapeutic target; novel; pre-clinical; presenilin-1; presenilin-2; prognostic value; response; stem cell model; synaptic function; targeted biomarker; tau Proteins; therapeutic target; transcriptomics; translational approach; trial design

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.

项目 3：新机制 项目摘要/摘要 最近，在了解淀粉样蛋白和 tau 蛋白变化轨迹方面取得了重大进展。 晚发型 (LOAD) 和常染色体显性 AD (ADAD)，明显建立了一个漫长的临床前阶段 在此期间，病理现象先于症状出现。虽然这两种形式的广告有许多共同点 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 LOAD 中发现的清除受损之外，β-淀粉样蛋白也存在。由于 AD 的两种形式都很复杂 尽管存在异质性，但为了加速治愈 AD 的进展，有必要对 AD 进行更全面的了解。 现在仍然面临着揭开引发和传播疾病的过程并评估其影响的挑战 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 了解追踪神经退行性变早期触发因素的其他分子过程，例如神经 炎症和突触损伤及其预示疾病进展的相关生物标志物。这 加速阿尔茨海默病药物合作 (AMP-AD) 联盟已确定分子 网络和新的目标生物标志物（包括那些涉及神经炎症和突触损伤的生物标志物） 死后加载脑组织。然而，对于 ADAD 中 APP、PSEN1 和 PSEN2 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 定义 ADAD 突变以及神经炎症和突触网络对疾病影响的方法 显性遗传性阿尔茨海默病网络 (DIAN) 参与者的进展，反过来，该网络将确定 新的疾病生物标志物。我们假设 ADAD 中的神经炎症过程（如直接定义） ADAD 大脑的分子分析以及通过其相关液体生物标志物在活体个体中检测到的 在疾病自然病程的早期发生改变，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[MS]的蛋白质组学）来定义炎症和突触网络 ADAD 大脑失调。与来自突变载体和同基因控制的网络数据配对 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，我们将创建一个系统的 分子相互作用图谱可阐明 ADAD 突变、炎症、突触功能、 以及相关的治疗目标。为了将 AD 脑网络信息转化为应用程序 具有潜在的临床相关性和实用性，在目标 2 中，从 DIAN 参与者纵向获得的 CSF 将是 通过 MS 和免疫分析对目标 1 中揭示的蛋白质以及几种“新兴”蛋白质进行询问 神经炎症生物标志物（YKL-40、sTREM2 和颗粒体蛋白前体）和突触损伤（VILIP-1、 神经颗粒素、SNAP-25、脑脊液 NfL 和血浆 NfL）已被证明在 LOAD 中具有实用性。