Structural basis of CD33 receptor signaling in Alzheimer's disease

项目摘要 阿尔茨海默病(AD)是一种致命的神经退行性疾病，65岁以上人口中有10%-30%的人会受到影响 很多年了。该病的病理特征是未能清除细胞外淀粉样蛋白(Aβ，Aβ)。 潮汐和细胞内神经原纤维从大脑中缠绕而来。在持续缺乏AD治疗的情况下， 疾病是持久的、致残的、代价高昂的，最终是致命的。小胶质细胞，中央的常驻吞噬细胞 神经系统，在清除Aβ聚集体中起着重要作用。激活状态与吞噬作用 小胶质细胞的功能受CD33细胞表面受体的调节。具体来说，AD风险等位基因 Rs3865444与抑制小胶质细胞吞噬功能的较高CD33水平有关。相比之下，CD33 灭活可改善吞噬功能并减轻β的病理改变。因此，抑制CD33可能代表了一种新的 阿尔茨海默病的治疗，为了帮助这一努力，目前的提案旨在了解阿尔茨海默病的结构基础 CD33信号。为了确定跨细胞膜的信号转导机制，在目标1中TM TM域的边界、TM域的聚集状态以及TM域和细胞域的结构和动力学。 Solic结构域将通过溶液核磁共振波谱来确定。连接配体结合和相关的生物- 结构事件的逻辑效应，提供了对TM信号机制的第一次洞察，在目标2中 两种胞质配体的CD33结合位点和亲和力将通过核磁共振和ITC进行表征。装订 这些位点进一步确定了胞质受体尾部的结构和功能作用，并提供了对AS- 胞质信号复合体。CD33属于唾液酸结合免疫球蛋白样家族 受体(Siglecs)调节先天和获得性免疫系统中细胞的功能，通过 识别它们的葡聚糖配体。这项拟议的研究提供了对鲜为人知的结构的基本见解- Siglec信号的现实基础，确定药物干预的靶点和序列 CD33信号转导，从而为治疗性AD干预提供了直接途径。

Project Summary Alzheimer's disease (AD) is a fatal neurodegenerative disorder that affects 10-30% of the population over 65 years old. The pathology of the disease is characterized by the failure to clear extracellular amyloid-β (Aβ) pep- tides and intracellular neurofibrillary tangles from the brain. In the continued absence of an AD therapy, the disease is persistent, disabling, costly and ultimately fatal. Microglia, the resident phagocytes of the central nervous system, play a major role in the clearance of Aβ aggregates. The activation state and phagocytosis capability of microglia are modulated by the CD33 cell-surface receptor. Specifically, the AD risk allele rs3865444 is associated with higher levels of CD33 that suppress microglial phagocytosis. In contrast, CD33 inactivation improves phagocytosis and mitigates Aβ pathology. CD33 inhibition may thus represent a novel therapy for AD and, to aid in this endeavor, the current proposals aims to understand the structural basis of CD33 signaling. To ascertain the mechanism of signal transduction across the cell membrane, in Aim 1 the TM domain border, the aggregation state of the TM domain, and the structure and dynamics of the TM and cyto- solic domains will be determined by solution NMR spectroscopy. To connect ligand binding and associated bio- logical effects with structural events that provide first insight into the mechanism of TM signaling, in Aim 2 the CD33-binding sites and affinities of two cytosolic ligands will be characterized by NMR and ITC. The binding sites further identify the structural and functional roles of the cytosolic receptor tail and provide insight into as- sembly of cytosolic signaling complexes. CD33 belongs to the family of sialic acid-binding immunoglobulin-like receptors (Siglecs) that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands. The proposed research provide basic insight into the little understood struc- tural basis of Siglec signaling, identifies targets sites and sequences for the pharmaceutical intervention in CD33 signaling and, thus, offers a direct avenue to therapeutic AD intervention.