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

批准号：
10679795
负责人：
Rocio Alejandra Barahona
金额：
$ 4.32万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679795
关键词：
Ablation Acceleration Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Behavioral Brain Cell Death Cells Central Nervous System Cerebral hemisphere Chondroitin Sulfate A Chondroitin Sulfate Proteoglycan Cognitive deficits Cytoprotection Data Dementia Deposition Development Disease Elderly Enhancers Enterobacteria phage P1 Cre recombinase Exhibits Extracellular Matrix Fluorescent in Situ Hybridization Genes Genetic Recombination Hippocampus Homeostasis Immunohistochemistry Immunologic Surveillance Impaired cognition Impairment Incubated Injections Interneurons Knowledge Laboratory Finding Learning LoxP-flanked allele Macrophage Mediating Mediator Memory Memory impairment Microglia Minor Modeling Mus Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurotoxins Outcome Oxidative Stress Parvalbumins Pathogenesis Pathologic Pathology Patients Play Population Predisposition Protease Inhibitor Protein Analysis Proteins Regulation Role Senile Plaques Structure Synapses Therapeutic Time Tissues Transgenic Organisms Viral Vector Virus Wild Type Mouse age related aggrecan effective therapy genome wide association study human tissue in vivo inhibitor therapy inhibitory neuron insight knockout gene memory consolidation mouse model nestin protein neuroinflammation neuron loss neuronal cell body novel therapeutics prevent transcriptome sequencing

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氏病（AD）是老种群中痴呆症的最常见原因。发展的发展由于我们缺乏对疾病的理解。 AD在经典的特征是淀粉样蛋白β（Aβ）斑块，神经纤维缠结，最终导致突触丧失，神经元功能障碍和认知的神经炎症障碍。凭借我们对这些病理出现的机制的不完整知识标志性，我们必须专注于理解疾病病理的不同方面，以成功创造治疗广告的疗法。基因组广泛的关联研究（GWAS）已经实施了小胶质细胞，该组织是组织居民大脑的巨噬细胞，作为疾病发病机理的介体。小胶质细胞积极维持组织稳态在健康的大脑中，包括调节晶格样细胞外基质（ECM）结构称为会内神经元网（PNN）。 pnns与不同的神经元子集的soma和近端突触和辅助在学习/记忆合并中。虽然PNN自然会随着野生型（WT）小鼠的年龄而损失，但这种损失是在广告中加重。有趣的是，当AD转基因5XFAD小鼠模型中消除小胶质细胞时，1）斑块未能形成，2）防止PNN损失，完全表明PNN起受保护的作用。然而， AD中PNN损失的后果仍然未知。为此，我们开发了两种方法在斑块沉积开始之前和之后烧毁PNN的结构，以确定其在斑块形成，突触损失和神经元损失。在此提案中，我将确定PNN在AD中的影响通过提出两个重要问题的病理：1）这些ECM结构的损失是否可以维持斑块形成和2）PNN损失是否会使神经元更容易受到损害？总的来说，该提议将通过探索如何在斑块病理开始之前和之后阐明PNN在AD中的作用 - 通过探索如何实验消融将影响牙菌斑沉积，突触损失和神经元丧失。确定是否PNNS 可以防止斑块沉积以及确定AD中的PNN损失是否使神经元更容易受到影响损害是高度相关的，可能导致针对涉及基因/蛋白质的新的治疗途径 PNN合成和降解。