Deciphering the Glycan Code in Human Alzheimer's Disease Brain

破译人类阿尔茨海默病大脑中的聚糖代码

• 批准号: 10779153
• 负责人: Peggi M Angel
• 金额: $ 79.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10779153
• 关键词: Deciphering; Glycan; Code; Human; Alzheimer

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.

抽象的： 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，以设计有效的疗法 除了众所周知的 AD 病理学之外， 葡萄糖代谢紊乱也是 AD 的一个临床特征，糖原和 N 连接聚糖是两个关键的特征。 糖原和 N 连接聚糖都很复杂，但尚未得到充分研究。 碳水化合物在认知、记忆形成和寿命等大脑生理学中发挥着重要作用。 尽管这些途径在正常大脑功能中很重要，但复杂的碳水化合物代谢是否 AD 疾病进展过程中受到的干扰仍然是神经生物学领域的一个关键知识空白。 初步数据，我们发现了深刻的糖原积累和蛋白质高糖基化 此外，我们在 AD 小鼠模型和人类 AD 标本的前额皮质中发现了阳性结果。 对 97 名患者进行的分析显示糖原增加与 Braak 分期之间的相关性 最后，口服。 葡萄糖胺补充剂，UDP-N-乙酰葡萄糖胺生物合成的前体，N-连接的构建块 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 基于这些初步数据，我们捕获了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。 必须解决复杂碳水化合物代谢紊乱的细胞和细胞外起源 我们将通过多参数的协同整合来实现这一目标。 首先，我们将通过临床定义复杂碳水化合物。 然后，我们将研究细胞和细胞外的情况。 最后，我们将应用多模态集成来跟踪正常和 AD 患者样本中的架构。 AD 中复杂碳水化合物扰动的细胞和细胞外起源（目标 3）。 关于理想的细胞、区域和时间特异性治疗机会的重要新信息 总的来说，我们相信该提案的结果对于 AD 的调节将非常重要。 阿尔茨海默病和其他神经退行性疾病的多个相关领域。