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

项目总结/摘要 阿尔茨海默病（AD）是全球痴呆症最常见的原因。在美国，它是第五大 是65岁以上人群的死亡原因。描述预测未来认知能力下降率的因素 和痴呆症是重要的，但尚未被彻底理解。 目前公认AD患者存在显著的临床异质性。这 异质性，尤其是AD进展速度的异质性，在设计和评价AD的治疗方案时， 新一代AD疗法的临床试验。驱动这种异质性的分子因素仍然很少 表征了已经注意到Aβ蛋白的几种翻译后修饰（PTM）影响了 Aβ聚集及其毒性的动物模型，从而可能影响AD的进展。研究 AD的动物和体外模型以及脑尸检标本已经注意到焦谷氨酰化Aβ PTM与 突触功能障碍和神经炎症。在人类中，焦谷氨酰化Aβ在影响 未来认知能力下降的速度尚不清楚。 本RO 3基础研究是一项临床转化研究，旨在表征 与神经炎症标志物相关的人类AD临床前阶段的焦谷氨酰化Aβ， 突触标记物和神经变性标记物，以了解它们对认知能力下降速度的影响。 该RO 3将帮助我们具体评估焦谷氨酰化Aβ对未来认知能力下降率的作用 在AD的临床前阶段的正常认知受试者中。我们假设，那些具有较高 CSF或血浆中基线焦谷氨酰化Aβ水平将具有更高水平的突触标志物，并且 神经炎性反应导致认知能力在两年内更快下降。通过同时评估 神经炎症、突触和神经退行性变相关的标记物纵向，我们将开发一个 焦谷氨酰化Aβ对临床前AD认知影响的机制模型。生物学知识 在人类中驱动AD进展的因素将在设计新的治疗策略中至关重要， 防止认知能力下降。 R 03还将为Pillai博士提供蛋白质组学方面的额外培训和研究机会， 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缺口 进展Pillai博士的长期目标是建立一个使用生物信息学的程序化研究机构 和蛋白质组学工具来描绘支持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.