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

总结/摘要：项目3大脑健康的精确生物标志物 项目3题为“大脑健康、年龄相关认知障碍和AD的精确生物标志物”， 评估影响人类整个生命周期认知健康的脑通路的新型CSF生物标志物。我们 我选择了三个生化和细胞途径，有很强的理由，从基本的 神经科学研究和最近的深层蛋白质组学分析在恢复力，生物体寿命， 和氧化还原平衡。这些途径也与认知的基本机制有很强的联系， 在衰老和AD大脑中被破坏。通路是根据每个细胞的核心关键分子来指定的。 三个目标。目的1关注NPTX 2（神经元五聚蛋白2），它在适应性神经元损伤中起着重要作用。 抑制回路在新皮层和海马中起作用以维持兴奋/抑制的稳态。 NPTX 2在与年龄相关的认知功能障碍（ARCI）中下调，在轻度认知功能障碍中被破坏。 损伤（MCI）和阿尔茨海默病（AD）。目标2关注mTORC 1（哺乳动物/机制靶点 雷帕霉素复合物1），介导神经元中的代谢稳态，与衰老有关， 在AD脑中被上调，在AD脑中被认为抑制自噬并有助于异常的细胞凋亡。 蛋白质的积累。目的3关注GDE 2（甘油磷酸二酯磷酸二酯酶2）， 调节控制APP的β-分泌酶（ADAM 10）加工的细胞外蛋白酶以及 通过GPI连接与质膜相连的蛋白质。GDE 2酶功能需要动态 氧化还原的控制。裂解底物在CSF中蓄积，并提供GDE 2功能和氧化还原的指示 体内平衡我们开发了平行反应监测质谱（PRM-MS）， 这些蛋白质与每一条通路相连。这些蛋白质构成了基于机制的生物标志物， 在项目2受试者样本队列的CSF中进行测定。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、非西班牙裔白色和非西班牙裔黑人个体 年龄在50-79岁之间。来自项目2的临床数据，检查认知功能和大脑 结构/功能连接，以及包括心血管疾病在内的风险因素的决定因素 将在项目4中评价葡萄糖不足、葡萄糖调节异常、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 这将为我们深入了解衰老过程，并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.