Deciphering the Glycan Code in Human Alzheimer's Disease Brain

摘要： 阿尔茨海默病（AD）是一种毁灭性的诊断，迫切需要了解其基本原理， AD的分子发病机制，以设计有效的治疗方法。除了众所周知的AD病理， 葡萄糖代谢紊乱也是AD的临床特征。糖原和N-连接聚糖是两个关键的 葡萄糖代谢的重要但未充分研究的方面。糖原和N-连接聚糖都是复杂的 碳水化合物在大脑生理学中起着至关重要的作用，如认知，记忆形成和寿命。 尽管这些途径在正常脑功能中的重要性， 在AD疾病进展期间受到干扰仍然是神经生物学中的关键知识缺口。以令人兴奋 初步的数据，我们发现了深刻的糖原积累和蛋白质高糖基化， AD小鼠模型和人类AD标本的前额叶皮质。此外，我们发现了一个积极的 97例患者队列分析中糖原增加与Braak分期之间的相关性。最后，口腔 葡萄糖胺补充剂，UDP-N-乙酰葡萄糖胺生物合成的前体，N-连接的 聚糖进一步加剧了高糖基化，并导致5xFAD小鼠的认知能力较差 AD模型基于这些初步数据，我们假设异常的复合碳水化合物 代谢是AD疾病进展过程中的致病过程。本研究的主要目的是 系统地解决复杂碳水化合物代谢紊乱的细胞和细胞外来源， 最先进的单细胞技术我们将通过多参数的协同整合来实现这一目标 单细胞质谱成像方法。首先，我们将定义复杂的碳水化合物与临床 患者样品中的病程和疾病进展（目标1）。然后，我们将询问细胞和细胞外 正常和AD患者样品中的结构（目的2）。最后，我们将应用多模态集成来跟踪 AD中复杂碳水化合物扰动的细胞和细胞外起源（目的3）。本研究将提供 关于理想的细胞，区域和时间特异性治疗机会的关键新信息 AD的调制总的来说，我们认为这项建议的结果将非常突出， 阿尔茨海默病和其他神经退行性疾病的多个相关领域。

Abstract: Alzheimer’s disease (AD) is a devastating diagnosis and there is a critical need to understand the fundamental molecular pathogenesis of AD to design effective therapies. In addition to the well-known AD pathologies, perturbed glucose metabolism is also a clinical feature of AD. Glycogen and N-linked glycans are two critically important but understudied facets of glucose metabolism. Both glycogen and N-linked glycans are complex carbohydrates that play vital roles in brain physiology such as cognition, memory formation, and life span. Despite the importance of these pathways in normal brain function, whether complex carbohydrate metabolism are perturbed during AD disease progression remains a critical knowledge gap in neurobiology. In exciting preliminary data, we discovered profound glycogen accumulation and protein hyperglycosylation in the prefrontal cortex of both mouse models of AD and human AD specimens. Further, we found a positive correlation between increased glycogen and Braak staging in an analysis of a 97-patient cohort. Finally, oral glucosamine supplement, a precursor to UDP-N-acetylglucosamine biosynthesis, building block of N-linked glycans further exacerbated hyperglycosylation and led to poorer cognitive performance in the 5xFAD mouse model of AD. Based on these preliminary data, we hypothesize that aberrant complex carbohydrate metabolism are pathogenic processes during AD disease progression. The major objective of this study is to systematically resolve cellular and extracellular origins of perturbed complex carbohydrate metabolism using state-of-the-art single cell technologies. We will achieve this through synergistic integration of multi-parameter single-cell mass spectrometry imaging methodologies. First, we will define complex carbohydrates with clinical course and disease progression in patient samples (Aim 1). Then, we will interrogate cellular and extra-cellular architecture in normal and AD patient samples (Aim 2). Finally, we will apply multimodal integration to track cellular and extracellular origins of complex carbohydrate perturbation in AD (Aim 3). This study will provide critical new information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic modulation of AD. Collectively, we believe the resultant findings from this proposal will be highly salient for multiple related fields of Alzheimer’s disease and other neurodegenerative disorders.