Defining the role of perineuronal nets in Alzheimer's Disease pathology

定义神经周围网在阿尔茨海默病病理学中的作用

基本信息

项目摘要

Project Summary Alzheimer’s Disease (AD) is the most common cause of dementia in elderly populations. The development of effective treatments for this progressive neurodegenerative disorder has been hindered by our lack of understanding of the disease. AD is classically characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and brain-wide neuroinflammation which ultimately result in synaptic loss, neuronal dysfunction, and cognitive impairments. With our incomplete knowledge of the mechanisms underlying the emergence of these pathological hallmarks, we must focus on understanding the different aspects of disease pathology to successfully create therapies treating AD. Genome wide association studies (GWAS) have implicated microglia, the tissue-resident macrophages of the brain, as mediators of disease pathogenesis. Microglia actively maintain tissue homeostasis in the healthy brain including the regulation of lattice-like extracellular matrix (ECM) structures called perineuronal nets (PNNs). PNNs enwrap the soma and proximal synapses of different neuronal subsets and aid in learning/memory consolidation. While PNNs are naturally lost with age in wild-type (WT) mice, this loss is exacerbated in AD. Interestingly, when microglia are eliminated in the AD transgenic 5xFAD mouse model, 1) plaques fail to form and 2) PNN loss is prevented, altogether suggesting PNNs play a protective role. However, the consequences of PNN loss in AD remain unknown. To that end, we have developed two approaches to ablate PNN structures both before and after the onset of plaque deposition in order to determine their role in plaque formation, synaptic loss, and neuronal loss. In this proposal, I will determine the impact of PNNs in AD pathology by pursuing two important questions: 1) does the loss of these ECM structures facilitate plaque formation and 2) does PNN loss make neurons more susceptible to damage? Collectively, this proposal will elucidate the role of PNNs in AD – before and after the onset of plaque pathology – by exploring how their experimental ablation will affect plaque deposition, synaptic loss, and neuronal loss. Establishing whether PNNs can prevent plaque deposition as well as determining whether PNN loss in AD renders neurons more susceptible to damage is highly relevant and could lead to new therapeutic avenues that target genes/ proteins involved in PNN synthesis and degradation.
项目摘要 阿尔茨海默病(AD)是老年人群中痴呆症的最常见原因。的发展 这种进行性神经退行性疾病的有效治疗由于我们缺乏 了解疾病。AD的典型特征是淀粉样蛋白-β(Aβ)斑块,神经纤维缠结, 和全脑神经炎症,最终导致突触丧失、神经元功能障碍和认知功能障碍。 损伤由于我们对这些病理性疾病出现的机制的不完全了解, 标志,我们必须专注于了解疾病病理学的不同方面,以成功地创建 治疗AD的方法。全基因组关联研究(GWAS)涉及小胶质细胞, 脑巨噬细胞,作为疾病发病机制的介质。小胶质细胞积极维持组织稳态 在健康的大脑中,包括调节称为细胞外基质(ECM)的网格状结构, 神经元束膜网(PNNs)。PNN包裹不同神经元亚群的索马和近端突触, 学习和记忆巩固的能力虽然PNN在野生型(WT)小鼠中随着年龄的增长而自然丢失,但这种丢失是在野生型小鼠中发生的。 在AD中恶化。有趣的是,当在AD转基因5xFAD小鼠模型中消除小胶质细胞时,1) 斑块不能形成和2)PNN损失被阻止,共同表明PNN起保护作用。然而,在这方面, AD中PNN丢失的后果仍然未知。为此,我们制定了两种方法, 在斑块沉积开始之前和之后消融PNN结构,以确定它们在 斑块形成、突触丧失和神经元丧失。在本提案中,我将确定PNN在AD中的影响 通过追求两个重要的问题:1)这些ECM结构的损失是否促进斑块 PNN的缺失是否会使神经元更容易受到损伤?总的来说,这项建议将 阐明PNNs在AD中的作用-斑块病理学发作之前和之后-通过探索它们如何在AD中发挥作用, 实验性消融将影响斑块沉积、突触损失和神经元损失。确定PNN是否 可以防止斑块沉积以及确定AD中PNN的丢失是否使神经元更易受影响 损伤是高度相关的,并可能导致新的治疗途径,靶向基因/蛋白质参与 PNN合成和降解。

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