Project 3: Precision biomarkers of Brain Health, Age-related Cognitive Impairment and AD

项目3：大脑健康、年龄相关认知障碍和AD的精准生物标志物

• 批准号: 10270197
• 负责人: PAUL F WORLEY
• 金额: $ 68.7万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270197
• 关键词: Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autophagocytosis; Biochemical; Biological Assay; Biological Markers; Blood; Brain; Categories; Cell membrane; Cleaved cell; Clinical Data; Cognition; Cognition Disorders; Cognitive; Cognitive aging; Collaborations; Companions; Complex; Coupled; Cross-Sectional Studies; Databases; Dementia; Disease; Extracellular Protein; FRAP1 gene; Functional Magnetic Resonance Imaging; GPI Membrane Anchors; Gene Expression; Glucose; Glycosylphosphatidylinositol Linkage; Growth Factor; Health; Hippocampus (Brain); Hispanics; Homeostasis; Human; Immune System Diseases; Impaired cognition; Individual; Inflammation; Integral Membrane Protein; Interneuron function; Latino; Link; Longevity; Mass Spectrum Analysis; Measures; Mediating; Mental Depression; Metabolic; Metabolism; Molecular Profiling; Monitor; Motor; Mus; Neocortex; Nerve Degeneration; Neurobiology; Neurons; Neurosciences Research; Not Hispanic or Latino; Oxidation-Reduction; Oxidative Stress; Parvalbumins; Pathway interactions; Peptide Hydrolases; Peripheral; Pharmacology; Plasma; Play; Process; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Publishing; Reaction; Research Personnel; Risk; Risk Factors; Role; Sampling; Signal Transduction; Social isolation; Stress; Structure; Technology; Testing; Therapeutic; Translations; age related; aged; amyloid precursor protein processing; asymptomatic Alzheimer' s disease; autism spectrum disorder; base; brain health; brain pathway; candidate marker; cardiovascular insufficiency; cognitive change; cognitive function; cognitive performance; cohort; extracellular; glycerophosphodiester phosphodiesterase; healthspan; hippocampal pyramidal neuron; insight; link protein; mild cognitive impairment; molecular marker; neuronal pentraxin; neuronal survival; non-demented; novel; peroxiredoxin; peroxiredoxin I; precision medicine; protein biomarkers; resilience; response; secretase; sensor; success; tau Proteins; tool; translational study

SUMMARY/ABSTRACT: Project 3 Precision Biomarkers of Brain Health Project 3 entitled “Precision biomarkers of brain health, age-related cognitive impairment and AD” will evaluate novel CSF biomarkers of brain pathways that impact human cognitive health across lifespan. We have selected three biochemical and cellular pathways that have strong rationale from fundamental neuroscience research and recent deep-proteomic analyses to play a role in resilience, organismal longevity, and redox homeostasis. These pathways also have a strong link to fundamental mechanisms of cognition and are disrupted in aging and AD brain. Pathways are designated based on key molecules that center each of three Aims. Aim 1 focuses on NPTX2 (Neuronal Pentraxin 2), which plays an essential role in adaptive inhibitory circuit function in neocortex and hippocampus to maintain homeostasis of excitation/inhibition. NPTX2 is down regulated with age-related cognitive impairment (ARCI) and disrupted in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Aim 2 focuses on mTORC1 (mammalian/mechanistic target of rapamycin complex 1), which mediates metabolic homeostasis in neurons, is implicated in aging and longevity, and is upregulated in AD brain where it is thought to inhibit autophagy and contribute to aberrant accumulation of proteins. Aim 3 focuses on GDE2 (Glycerophosphodiester phosphodiesterase 2), which regulates extracellular proteases that control -secretase (ADAM10) processing of APP as well as a host of proteins that are tethered to the plasma membrane by GPI linkage. GDE2 enzymatic function requires dynamic control of redox. Cleaved substrates accumulate in CSF and provide an indication of GDE2 function and redox homeostasis. We have developed parallel reaction monitoring mass spectroscopy (PRM-MS) to quantitate proteins linked to each of these pathways. These proteins constitute mechanism-based biomarkers that will be assayed in CSF from the cohort of subject samples from Project 2. We estimate this will include ~800 samples from approximately equal numbers of Hispanic/Latino, Non-Hispanic White, and non-Hispanic Black individuals in the age range of 50-79. Clinical data from Project 2 examining cognitive function and brain structure/functional connectivity, together with determinants of risk factors including cardiovascular insufficiency, glucose dysregulation, inflammation and immune dysfunction will be evaluated in Project 4 together with blood and sweat biomarkers. Studies will identify cross-sectional and longitudinal correlations that will provide insight into the aging process and provide a rational basis for precision medicine of aging.

摘要/摘要：项目3大脑健康的精确生物标志物 项目3标题为“大脑健康，与年龄有关的认知障碍和AD的精确生物标志物”将 评估脑途径的新型CSF生物标志物，影响整个生命周期的人类认知健康。我们 已经选择了三种生化和细胞途径，这些途径具有很强的基本原理 神经科学研究和最近的深度蛋白质分析在弹性，有机寿命中发挥作用， 和氧化还原稳态。这些途径还与认知的基本机制和 在衰老和广告大脑中受到破坏。途径是基于关键分子设计的，该分子中心 三个目标。 AIM 1专注于NPTX2（Neuronal Pentraxin 2），在适应性中起着至关重要的作用 新皮层和海马中的抑制回路功能维持兴奋/抑制的体内稳态。 NPTX2受年龄相关的认知障碍（ARCI）的调节，并在轻度认知中受到干扰 障碍（MCI）和阿尔茨海默氏病（AD）。 AIM 2专注于MTORC1（哺乳动物/机械目标 雷帕霉素综合体1）介导神经元中代谢稳态的介导的含量在衰老中暗示 寿命，并在广告大脑中进行更新，该广告被认为会抑制自噬并导致异常 蛋白质的积累。 AIM 3专注于GDE2（甘油磷酸二酯酶2），其中 调节控制应用程序处理-分泌酶（ADAM10）的细胞外蛋白酶以及宿主 通过GPI链接束缚在质膜上的蛋白质。 GDE2酶函数需要动态 控制氧化还原。切割的底物积累在CSF中，并提供了GDE2功能和氧化还原的指示 稳态。我们已经开发了平行反应监测质谱（PRM-MS）以定量 蛋白质连接到这些途径中的每一种。这些蛋白质构成基于机制的生物标志物 从项目2中的主题样本组中在CSF中进行测定。我们估计这将包括〜800个样品 来自大约相等数量的西班牙裔/拉丁裔，非西班牙裔白人和非西班牙裔黑人 在50-79岁的年龄范围内。项目2的临床数据检查认知功能和大脑 结构/功能连接，以及包括心血管在内的风险因素的决定剂 项目4将评估功能不全，葡萄糖失调，炎症和免疫功能障碍 研究将确定横截面和纵向相关性 这将提供对衰老过程的见解，并为衰老的精确医学提供合理的基础。