Leveraging Heterogeneity in Autosomal Dominant AD to Elucidate Pathophysiology and Improve AD Biomarkers

利用常染色体显性 AD 的异质性阐明病理生理学并改善 AD 生物标志物

• 批准号: 10539956
• 负责人: JASMEER P CHHATWAL
• 金额: $ 435.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539956
• 关键词: Abeta synthesis; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biochemical; Biological; Biological Markers; Biological Models; Biology; Calcium; Catalytic Domain; Cell membrane; Cells; Classification; Clinical Trials; Cognitive; Complex; DNA Sequence Alteration; Data; Development; Disease; Early Onset Alzheimer Disease; Equilibrium; Event; Family Caregiver; Family health status; Functional disorder; Grouping; Healthcare Systems; Heterogeneity; Hippocampus (Brain); Homeostasis; Human Amyloid Precursor Protein; Immunoassay; In Vitro; Inherited; International; Investigation; Kinetics; Knockout Mice; Mass Spectrum Analysis; Measures; Membrane; Modeling; Mutation; Nerve Degeneration; Neurons; Observational Study; Outcome; Pathogenicity; Pathologic; Patients; Penetrance; Positron-Emission Tomography; Production; Symptoms; Syndrome; Testing; Therapeutic; Translating; Variant; autosomal dominant Alzheimer' s disease; base; biomarker development; conditional knockout; cost effective; drug development; enzyme substrate; gamma secretase; genetic variant; improved; in vivo; mutant; novel; presenilin-1; response; success; tau phosphorylation; therapeutic development; treatment effect; variant of unknown significance

Project Abstract: Alzheimer’s disease (AD) and related dementias (ADRD) represent an enormous burden for patients, families, and health care systems, underscoring the urgent need for efficacious, widely-accessible, and cost- effective disease-modifying therapies. The over-production of longer, aggregation-prone Ab fragments (esp. Ab42 and 43) relative to shorter, non-aggregating fragments (esp. Ab37 and 38) appears to be a critical initiating pathological event in both late-onset, sporadic AD (LOAD) and Autosomal Dominant AD (ADAD). The balance between production of aggregating and non-aggregating forms of Ab is a direct result of the efficiency and kinetics with which the γ-secretase complex sequentially cleaves b-amyloid precursor protein (APP). Subtle alterations in γ-secretase function can have profound neurodegenerative and cognitive consequences, while modulation of γ-secretase has therapeutic potential in both LOAD and ADAD. Over 200 pathogenic variants in Presenilin-1 (PS1), the key catalytic subunit in the γ-secretase complex, have been identified and are the most common cause of ADAD. Despite near complete penetrance, there is substantial heterogeneity in age of symptom onset (a range of >30 years) and rates of cognitive and biomarker change between PS1 variants. In this proposal, we hypothesize that differences in γ-secretase function between ADAD-causing PS1 mutations measured in cell-based, biochemical, and primary neuronal model systems will help explain heterogeneity in age of symptom onset, cognitive, and biomarker changes seen in PS1 pathogenic variant carriers in vivo. We test this hypothesis through systematic characterization of γ-secretase function across PS1 pathogenic variants and comparing the resulting immunoassay and mass spectroscopy measures of g-secretase function to cognitive and biomarker data from carriers of corresponding PS1 variants participating in the Dominantly Inherited Alzheimer’s Network Observational Study (DIAN-Obs), a large international study in which over 80 unique PS1 pathogenic variants are represented. Determining which variant-specific differences in γ-secretase function translate into differences in age of symptom onset and cognitive and biomarker trajectories in PS1 carriers represents a unique opportunity to elucidate AD pathobiology, inform therapeutic and biomarker development, and impact ADAD clinical trials.

项目摘要： 阿尔茨海默氏病（AD）和相关痴呆症（ADRD）代表患者的巨大烧伤， 家庭和卫生保健系统，强调了迫切需要高效，广泛且成本的需求 有效改善疾病的疗法。较长，容易发生的AB片段的过度生产（尤其是。 AB42和43）相对于较短的，非聚集的片段（尤其是AB37和38）似乎是关键 在晚期，零星AD（负载）和常染色体显性AD（ADAD）中启动病理事件。 AB的汇总和非聚集形式的生产之间的平衡是 γ-分泌酶复合物顺序切割B-淀粉样蛋白蛋白的效率和动力学 （应用程序）。 γ-分泌酶功能的细微变化可以具有深刻的神经退行性和认知能力 后果，而γ-分泌酶的调节在负载和ADAD中具有治疗潜力。超过200 Presenilin-1（PS1）（γ-分泌酶复合物中的关键催化亚基）中的致病变异已是 确定，是ADAD的最常见原因。尽管几乎完全渗透，但仍有大量 症状发作时代的异质性（超过30岁）和认知和生物标志物变化的速度 在PS1变体之间。在此提案中，我们假设γ-分泌酶功能之间的差异 在基于细胞，生化和原发性神经元模型系统中测得的ADAD引起的PS1突变将 帮助解释症状发作，认知和生物标志物变化的异质性 病原变体载体在体内。我们通过γ-分泌酶的系统表征检验这一假设 PS1致病变异的功能，并比较所得的免疫测定法和质谱法 从相应PS1变体的载体中g-分泌酶函数对认知和生物标志物数据的度量 参加主要继承的阿尔茨海默氏症网络观察研究（Dian-Obs），这是一个大型 国际研究代表了80多种独特的PS1致病变体。确定哪个 γ-分泌酶功能的变异特异性差异转化为症状发作时代的差异和 PS1载体中的认知和生物标志物轨迹代表了阐明AD的独特机会 病理生物学，信息治疗和生物标志物的发展以及影响ADAD临床试验。