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

摘要/摘要：脑健康的精密生物标记物项目3 题为《脑健康、年龄相关认知障碍和阿尔茨海默病的精确生物标志物》的项目3将 评估影响人类终身认知健康的脑通路的新型脑脊液生物标记物。我们 我选择了三个生化和细胞途径，从根本上有很强的理论基础 神经科学研究和最新的深层蛋白质组分析在弹性、生物长寿、 和氧化还原动态平衡。这些途径也与基本的认知机制和 在衰老和阿尔茨海默病的大脑中被破坏。通路是根据关键分子指定的 三个目标。目的1重点研究NPTX2(神经元五角蛋白2)，它在适应中起重要作用 抑制回路在大脑皮层和海马区发挥作用，维持兴奋/抑制的动态平衡。 NPTX2在年龄相关认知障碍(ARCI)中表达下调，在轻度认知障碍中表达中断 损害(MCI)和阿尔茨海默病(AD)。目标2侧重于mTORC1(哺乳动物/机械性靶标 雷帕霉素复合体1)，它调节神经元的代谢动态平衡，与衰老和 长寿，并在AD大脑中上调，被认为抑制自噬并导致异常 蛋白质的积累。目的3研究GDE2(甘油磷酸二酯酶2)。 调节控制-分泌酶(ADAM10)处理的胞外蛋白水解酶以及许多 通过GPI连接到质膜上的蛋白质。GDE2酶功能需要动态 控制氧化还原。裂解底物在脑脊液中积累，并提供GDE2功能和氧化还原的指示 动态平衡。我们已经建立了平行反应监测质谱学(PRM-MS)来定量 与这些途径中的每一个相关联的蛋白质。这些蛋白质构成了基于机制的生物标记物， 在脑脊液中从项目2的受试者样本队列中进行检测。我们估计这将包括大约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个体 年龄在50-79岁之间。项目2检查认知功能和大脑的临床数据 结构/功能连接，以及包括心血管在内的风险因素的决定因素 在项目4中将评估功能不全、葡萄糖调节失调、炎症和免疫功能障碍 以及血液和汗液的生物标记物。研究将确定横截面和纵向的相关性 这将为了解衰老过程提供洞察，为衰老的精准医学提供合理的依据。

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.