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 大脑健康的精准生物标志物 题为“大脑健康、年龄相关认知障碍和 AD 的精确生物标志物”的项目 3 将 评估影响人类整个生命周期认知健康的大脑通路的新型脑脊液生物标志物。 选择了三种具有强有力的基本原理的生化和细胞途径 神经科学研究和最近的深层蛋白质组学分析在恢复力、生物寿命、 这些途径也与认知和氧化还原稳态的基本机制有密切的联系。 衰老和 AD 大脑中的通路被破坏，通路是根据每个通路的关键分子来指定的。 三个目标 1 重点关注 NPTX2（神经元 Pentraxin 2），它在适应性中发挥着重要作用。 新皮质和海马体中的抑制回路发挥作用，维持兴奋/抑制的稳态。 NPTX2 在年龄相关认知障碍 (ARCI) 中下调，在轻度认知障碍中受到干扰 损伤 (MCI) 和阿尔茨海默病 (AD) 目标 2 重点关注 mTORC1（哺乳动物/机械靶标）。 雷帕霉素复合物 1) 介导神经元代谢稳态，与衰老和衰老有关 长寿，并且在 AD 大脑中表达上调，被认为可以抑制自噬并导致异常 目标 3 关注 GDE2（甘油磷酸二酯磷酸二酯酶 2），它 调节控制 APP 的 α-分泌酶 (ADAM10) 加工的细胞外蛋白酶以及许多 通过 GPI 连接与质膜相连的蛋白质需要动态的 GDE2 酶促功能。 控制氧化还原作用，在 CSF 中积累并提供 GDE2 功能和氧化还原的指示。 我们开发了平行反应监测质谱 (PRM-MS) 来定量。 与这些途径中的每一个相关的蛋白质这些蛋白质构成了基于机制的生物标志物。 从项目 2 的受试者样本队列中进行脑脊液检测。我们估计这将包括约 800 个样本 来自大约相同数量的西班牙裔/拉丁裔、非西班牙裔白人和非西班牙裔黑人 项目 2 的临床数据检查认知功能和大脑，年龄范围为 50-79 岁。 结构/功能连接，以及包括心血管在内的危险因素的决定因素 不足、葡萄糖失调、炎症和免疫功能障碍将在项目 4 中进行评估 与血液和汗液生物标志物一起研究将确定横截面和纵向相关性。 这将有助于深入了解衰老过程，并为衰老精准医学提供合理基础。