Glycosylation of the perineuronal net in Alzheimer's Disease

阿尔茨海默病中神经周围网络的糖基化

• 批准号: 9785861
• 负责人: Jeffrey D Esko
• 金额: $ 46万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9785861
• 关键词: Acetylgalactosamine; Acids; Age; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Attenuated; Basement membrane; Behavioral; Biological Neural Networks; Blocking Antibodies; Brain; Brain Diseases; Calcium-Binding Proteins; Carbon; Cells; Chondroitin Sulfate A; Chondroitin Sulfate Proteoglycan; Chondroitin Sulfates; Code; Cognitive; Communication; Core Protein; Data; Disaccharides; Electrophysiology (science); Enzymes; ErbB4 gene; Extracellular Matrix; Family; Frequencies; Generations; Genetic; Glycosaminoglycans; Goals; Heparan Sulfate Proteoglycan; Human; Hyaluronan; Impairment; Interneurons; Language; Length; Lyase; Maintenance; Mediating; Memory Loss; Metalloproteases; Molecular; Molecular Analysis; Morphology; Mus; Mutant Strains Mice; Mutate; Myeloid Cells; Neprilysin; Neurodegenerative Disorders; Neuroglia; Neuronal Plasticity; Optics; Parvalbumins; Pathogenesis; Pathway interactions; Pattern; Play; Proteins; Reporting; Research; Research Priority; Role; Sampling; Serum; Signal Transduction; Specificity; Spinal Cord; Synapses; Tenascin; Unspecified or Sulfate Ion Sulfates; Viral; axon growth; axon regeneration; base; beta-site APP cleaving enzyme 1; biomarker discovery; brain volume; cholinergic neuron; cognitive function; depolymerization; glycoproteomics; glycosylation; improved; insight; interstitial; link protein; long term memory; member; mouse model; neuropathology; overexpression; programs; receptor; relating to nervous system; response; spatiotemporal; sugar; tau Proteins; therapeutic target

Abstract The long-term goal of this project is to determine the role of the perineuronal net (PNN) and its glycosylation in Alzheimer's Disease (AD) in response to one of the High-Priority Research Topics for PAR-18-596, namely “Deciphering the Glycosylation Code of Alzheimer's Disease”. Glycomics (glycosylation or sugar codes) are the third molecular language of cells. Recent data suggest that glycosylation pathways play a role in AD and have emerged as an area of research for understanding and developing treatments of AD. For example, many key proteins associated with AD are glycosylated, including amyloid precursor protein, BACE1, neprilysin (NEP) and triggering receptor expressed in myeloid cells. PNN is a lace-like cloak of ECM enwraping primarily a selective class of fast-spiking inhibitory interneurons expressing calcium binding protein parvalbumin (PV). The PNN is primarily comprised of members of the lectican family of chondroitin sulfate proteoglycans (CSPGs), hyaluronan, tenascins and link proteins. The CSPGs are an array of core proteins attached with varying lengths of CS, which is a glycosaminoglycan composed of disaccharide units formed by glucurionic acid (GlcA) and N-acetylgalactosamine (GalNAc). Several lines of evidence support that PNN plays a role in AD and may be a therapeutic target. First, PNN is significantly reduced in the AD brain. It has been postulated by Roger Tsien that very long-term memories may be stored in the pattern of holes in the PNN. Second, recent data demonstrate that PNN is exclusively associated with PV+ interneurons expressing metallopeptidases Adamts8, Adamts15 and NEP. NEP is one of the most potent Aβ-degrading enzymes. The impairment of neural network oscillations at different frequencies that mediate local and long-range communications for brain functions leads to cognitive and behavioral deficits in AD. These PV+ play essential roles in the generation of γ- frequency neural network oscillations. Optical activation of PV+ interneurons at γ-frequencies has been shown to attenuate amyloid load and improve cognitive function. Finally, GlcA and GalNAc at carbons C4, C6, and C2 may be sulfated in either combination and has profound effects on synaptic integrity and function. It has been reported that 4-sulfate chondroitin (C4S) inhibits axonal growth and neural plasticity while C6S promotes axon regeneration and neural plasticity. Moreover, C4S blocking antibodies have been explored to alleviate neuropathology in mouse overexpressing mutated Tau protein. Finally, preliminary results showed aberrant γ- oscillations associated with impairment of PNN and PV+ interneurons in AD mouse model line 41. Furthermore, viral-mediated over-expression of neuregulin1 (NRG1) ameliorates neuropathology and improves cognitive function in line 41 mice. Brain cholinergic neuron-specific NRG1 mutant mice display impaired PNN. Based on these results, Aim 1 is to characterize the PNN state of glycosylation during progression of AD. Aim 2 is to determine whether manipulation of PNN glycosylation modifies progression of AD. Aim 3 is to determine the role of NRG1 signaling in the formation and maintenance of the PNN.

摘要 该项目的长期目标是确定神经周围神经网络(PNN)及其糖基化在 阿尔茨海默病(AD)对PAR-18-596高优先级研究主题之一的响应，即 《破译阿尔茨海默病的糖基化密码》。糖链(糖基化或糖码)是 细胞的第三种分子语言。最近的数据表明，糖基化途径在AD和 已经成为了解和开发AD治疗方法的一个研究领域。例如，许多 与AD相关的关键蛋白是糖基化的，包括淀粉样前体蛋白、BACE1、Neprilysin (NEP)和触发受体在髓系细胞中表达。PNN主要是一种花边状的ECM包裹斗篷 一类选择性的表达钙结合蛋白小白蛋白(PV)的快峰抑制中间神经元。 PNN主要由硫酸软骨素蛋白多糖的凝集素家族成员组成。 (CSPGs)、透明质酸、Tenascins和链接蛋白。CSPG是一组连接在一起的核心蛋白 不同长度的CS，它是由葡萄糖醛酸离子形成的二糖单元组成的糖胺聚糖 酸(GLCA)和N-乙酰半乳糖胺(GalNAc)。有几条证据支持PNN在 并可能成为治疗的靶点。首先，阿尔茨海默病患者大脑中的PNN显著减少。这是一种假设 罗杰·钱存训认为，非常长期的记忆可能存储在PNN上的孔洞模式中。第二，最近 研究表明，PNN仅与表达金属肽酶的PV+中间神经元有关 Adamts8、Adamts15和NEP。NEP是最有效的Aβ降解酶之一。减损 神经网络在不同频率下的振荡，调节大脑的局部和远程通信 功能障碍会导致AD患者的认知和行为缺陷。这些PV+在γ-的产生中起着至关重要的作用 频率神经网络振荡。γ频率下PV+中间神经元的光激活 减轻淀粉样蛋白负荷，改善认知功能。最后，碳C4、C6和C2上的Glca和GalNAc 可以在任何一种组合中被硫酸盐化，并对突触的完整性和功能有深远的影响。一直以来 报道4-硫酸软骨素(C4S)抑制轴突生长和神经可塑性，而C6S促进轴突 再生和神经可塑性。此外，C4S封闭抗体已经被探索用来缓解 过表达突变Tau蛋白的小鼠的神经病理学。最后，初步结果显示异常的γ- AD小鼠模型系41中与PNN和PV+中间神经元损伤相关的振荡。此外， 病毒介导的神经调节蛋白1(NRG1)过表达改善神经病理和改善认知功能 在41系小鼠中起作用。脑胆碱能神经元特异性NRG1突变小鼠表现出PNN受损。基于 这些结果，目的1是表征AD进展过程中糖基化的PNN状态。目标2是 确定操纵PNN糖基化是否改变AD的进展。目标3是确定 NRG1信号在PNN的形成和维持中的作用。