Pyroglutamate-modified Amyloid-B protein as a marker for future cognitive decline in preclinical Alzheimers disease

项目摘要/摘要 阿尔茨海默病(AD)是全球最常见的痴呆症病因。在美国，它是第五大领头羊 65岁以上老人的死因。描述预测未来认知功能减退率的因素 和痴呆症很重要，但还没有完全了解。 现在已经很好地认识到，AD患者之间存在着显著的临床异质性。这 异质性，特别是AD进展速度的异质性，在设计和评估中带来了巨大的挑战 新一代阿尔茨海默病疗法的临床试验。驱动这种异质性的分子因素仍然很差。 特色化的。已经注意到β蛋白的几个翻译后修饰(PTM)会影响这一速度 Aβ聚集性及其在动物模型中的毒性，从而可能影响AD的进展。研究：关于 动物和体外AD模型和脑尸检标本注意到焦谷氨酰化AβPTMS与 到突触功能障碍和神经炎症。在人类中，焦谷氨酰化Aβ在影响 未来认知功能下降的速度是未知的。 这项RO的基础研究是一项临床转化性研究，旨在表征这些水平 人类阿尔茨海默病临床前阶段焦谷氨酰化A-β与神经炎症标志物的关系 突触标记物和神经退行性标记物，以了解它们对认知衰退速度的影响。 这个RO_3将帮助我们具体评估焦谷氨酰化A-β对未来认知减退率的作用 在阿尔茨海默病临床前期正常认知受试者中。我们假设，那些拥有更高 脑脊液或血浆中焦谷氨酰化A-β的基线水平会有更高水平的突触标志物，并且 神经炎性反应在两年内导致认知能力更快的下降。通过同时评估 在纵向上，我们将开发一种与神经炎性、突触和神经变性相关的标记物 焦谷氨酰化A-β的机制模型S对临床前AD患者认知功能的影响 推动人类阿尔茨海默病进展的因素将是设计新的治疗策略的关键 防止认知能力下降。 R03还将有助于为Pillai博士提供额外的蛋白质组学培训和研究机会 提高他的临床研究技能以解决目前在影响AD的分子因素方面的知识差距 进步。皮莱博士的长期目标是利用生物信息学建立一个有计划的研究机构 和蛋白质组学工具来描绘支撑疾病进展的分子因素 神经退行性疾病和开发治疗策略。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline and dementia are important but are yet to be thoroughly understood. It is now well recognized that there is substantial clinical heterogeneity among patients with AD. This heterogeneity particularly in rate of AD progression entails a significant challenge in designing and evaluating clinical trials for a new generation of AD therapies. Molecular factors that drive this heterogeneity are still poorly characterized. Several post translational modifications (PTMs) of Aβ protein have been noted to impact the rate of Aβ aggregation and its toxicity in animal models and thereby potentially impact AD progression. Studies on animal and in vitro models of AD and brain autopsy specimens have noted pyroglutamylated Aβ PTMs as relating to synaptic dysfunction and neuroinflammation. Among humans, the role for pyroglutamylated Aβ in impacting future rate of cognitive decline is unknown. The research at the foundation of this RO3 is a clinical translational study that aims to characterize the levels pyroglutamylated Aβ at the preclinical stage of AD among humans, in relation to neuroinflammation markers, synaptic markers and neurodegeneration markers to understand their impact on the rate of cognitive decline. This RO3 will help us specifically evaluate the role for pyroglutamylated Aβ on future rate of cognitive decline among normal cognition subjects at the preclinical stage of AD. We hypothesize that those subjects with higher levels of pyroglutamylated Aβ at baseline in the CSF or plasma will have higher levels of synaptic markers, and neuroinflammatory response contributing to faster cognitive decline over two years. By concurrently evaluating the neuroinflammatory, synaptic and neurodegeneration related markers longitudinally, we will develop a mechanistic model of pyroglutamylated Aβ's impact on cognition in preclinical AD. Knowledge of biological factors that drive AD progression among humans will be critical in designing novel therapeutic strategies to prevent cognitive decline. This R03 will also help provide additional training and research opportunities in proteomics for Dr. Pillai to advance his clinical research skills to address a current knowledge gap in the molecular factors impacting in AD progression. The long-term goal of Dr. Pillai is to establish a programmatic body of research using bioinformatics and proteomics tools to delineate the molecular factors that underpin disease progression among neurodegenerative diseases and develop therapeutic strategies.