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元周网（PNN）及其糖基化在神经元损伤中的作用。 阿尔茨海默病（AD）响应PAR-18 - 596的高优先级研究课题之一，即 阿尔茨海默病的病因是什么？糖组学（糖基化或糖代码）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中起作用， 已经成为理解和开发AD治疗的研究领域。比如很多 与AD相关的关键蛋白质是糖基化的，包括淀粉样前体蛋白、BACE1、脑啡肽酶 (NEP)和在骨髓细胞中表达的触发受体。PNN是一种花边状的ECM斗篷， 一种选择性的表达钙结合蛋白小清蛋白（PV）的快速尖峰抑制性中间神经元。 PNN主要由硫酸软骨素蛋白聚糖的凝集素家族的成员组成 （CSPG）、透明质酸、腱生蛋白和连接蛋白。CSPG是一系列核心蛋白， 不同长度的CS，其是由葡萄糖醛酸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）。几条证据支持PNN在以下方面发挥作用： AD，可能是治疗靶点。首先，PNN在AD脑中显著减少。据推测 Roger Tsien提出，非常长期的记忆可以存储在PNN中的孔模式中。第二，近期 数据表明PNN仅与表达金属肽酶的PV+中间神经元相关 Adamts8，Adamts15和NEP。NEP是最有效的A β降解酶之一。减值 不同频率的神经网络振荡，介导大脑的本地和远程通信 功能导致AD中的认知和行为缺陷。这些PV+在γ-的产生中起着重要的作用。 频率神经网络振荡。PV+中间神经元在γ频率下的光学激活已经被证明是 减轻淀粉样蛋白负荷并改善认知功能。最后，在碳C4、C6和C2处的GlcA和GalNAc 可以在任一组合中被硫酸化，并且对突触的完整性和功能具有深远的影响。已经 报道4-硫酸软骨素（C4S）抑制轴突生长和神经可塑性，而C6S促进轴突生长和神经可塑性。 再生和神经可塑性。此外，已经探索了C4S阻断抗体以减轻 神经病理学的小鼠过表达突变的Tau蛋白。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，委员会认为， 病毒介导的神经调节蛋白1（NRG 1）过表达可改善神经病理学并改善认知功能 在41号线小鼠中的功能。脑胆碱能神经元特异性NRG1突变小鼠显示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。目标二是 确定PNN糖基化的操作是否改变AD的进展。目标3是确定 NRG1信号在PNN形成和维持中的作用。