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.

项目概要阿尔茨海默病（AD）是老年人痴呆症的最常见原因。由于我们缺乏治疗方法，这种进行性神经退行性疾病的有效治疗受到阻碍 AD 的典型特征是淀粉样蛋白-β (Aβ) 斑块、神经原纤维缠结、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障碍由于我们对这些病理现象出现的机制还不完全了解。标志，我们必须重点了解疾病病理学的不同方面才能成功创造治疗 AD 的疗法涉及小胶质细胞（组织驻留体）。大脑巨噬细胞作为疾病发病机制的介质，积极维持组织稳态。在健康大脑中，包括对称为“格子状细胞外基质”（ECM）结构的调节神经周围网 (PNN) 包裹不同神经元亚群的胞体和近端突触并提供帮助。虽然野生型 (WT) 小鼠的 PNN 会随着年龄的增长而自然丧失，但这种丧失是当 AD 转基因 5xFAD 小鼠模型中的小胶质细胞被消除时，AD 中的症状会加剧，1) 斑块无法形成，并且 2) PNN 损失被阻止，这表明 PNN 发挥了保护作用。 AD 中 PNN 丢失的后果仍然未知。为此，我们开发了两种方法。在斑块沉积开始之前和之后消融 PNN 结构，以确定它们在斑块沉积中的作用在本提案中，我将确定 PNN 在 AD 中的影响。通过追寻两个重要问题来进行病理学研究：1）这些 ECM 结构的丧失是否会促进斑块的形成 2）PNN 损失是否会使神经元更容易受到损伤？通过探索 PNN 在斑块病理发生之前和之后如何作用，阐明 PNN 在 AD 中的作用实验性消融会影响斑块沉积、突触损失和神经损失。可以防止斑块沉积，并确定 AD 中 PNN 缺失是否会使神经元更容易受到影响与损伤高度相关，并可能导致针对参与损伤的基因/蛋白质的新治疗途径 PNN 合成和降解。