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

项目摘要 阿尔茨海默病(AD)是老年人痴呆症最常见的原因。的发展。 这种进行性神经退行性疾病的有效治疗因我们缺乏 对疾病的了解。AD的典型特征是淀粉样蛋白(Aβ，Aβ)斑块、神经原纤维缠结、 以及全脑神经炎，最终导致突触丧失、神经元功能障碍和认知 减损。由于我们对这些病理性疾病产生的机制了解不够全面 标志，我们必须专注于了解疾病病理的不同方面，才能成功地创造 治疗阿尔茨海默病的疗法。全基因组关联研究表明，小胶质细胞是一种组织驻留细胞 脑内巨噬细胞，作为疾病发病机制的介体。小胶质细胞积极维持组织内环境平衡 在健康的大脑中，包括对晶格状细胞外基质(ECM)结构的调节，称为 周围神经网(PNNS)。三叉神经核包裹不同神经元亚群的胞体和近端突触 在学习/记忆巩固方面。虽然野生型(WT)小鼠的PNN会随着年龄的增长而自然丢失，但这种丢失是 在公元后恶化。有趣的是，在AD转基因5xFAD小鼠模型中，当小胶质细胞被消除时，1) 斑块不形成，2)PNN丢失被阻止，提示PNNS具有保护作用。然而， AD中PNN丢失的后果尚不清楚。为此，我们开发了两种方法来 在斑块沉积开始前后消融PNN结构，以确定它们在 斑块形成、突触丢失和神经元丢失。在这份提案中，我将确定PNNS在AD中的影响 1)这些细胞外基质结构的丧失是否促进了斑块的形成 形成和2)PNN丢失是否使神经元更容易受到损伤？总体而言，这项提议将 通过探讨PNNS在AD斑块病理发生前后的作用，阐明PNNS在AD中的作用 实验性消融会影响斑块沉积、突触丢失和神经元丢失。确定PNNS是否 可以防止斑块沉积，并确定AD中PNN的丢失是否会使神经元更容易受到影响 损伤是高度相关的，并可能导致针对参与其中的基因/蛋白质的新的治疗途径 PNN的合成和降解。

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.