Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease

少突胶质细胞来源的 IL-33 在大脑衰老和阿尔茨海默病中的作用

基本信息

批准号：
10670496
负责人：
Shin H Kang
金额：
$ 53.39万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670496
关键词：
1 year old APP-PS1 Abeta clearance Ablation Acute Affect Affinity Chromatography Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Astrocytes Axon Bacterial Artificial Chromosomes Biological Response Modifiers Brain Cell Communication Cells Cognitive Cognitive deficits Communication Complex Demyelinations Deposition Development Disease Disease Progression Emotional Family Family member Functional disorder Genetic Genetic Variation Genetically Engineered Mouse Injury Interleukin-1 Interleukins Knowledge Maintenance Mediating Metabolic Microglia Molecular Morphology Motor Mus Myelin Myelin Sheath Natural regeneration Nature Neuraxis Neuroglia Neuroimmune Neuroimmunomodulation Neurons Nuclear Nutritional Support Oligodendroglia Organ Patients Peripheral Play Population Process Production Property Regulation Resolution Ribosomes Risk Role Senile Plaques Sensory Serum Source Stress Stress and Coping System Testing Therapeutic Time Translating abeta deposition age related age related neurodegeneration aged aging brain amyloid pathology brain shape cell type central nervous system injury cohort conditional knockout coping coping mechanism cytokine disease phenotype experimental study extracellular genetic manipulation injury and repair macroglia member mouse genetics mouse model neural circuit neural repair neuroinflammation normal aging novel oligodendrocyte lineage overexpression programs receptor regenerative repaired response selective expression single-cell RNA sequencing synaptic pruning targeted treatment tool transcriptome transcriptome sequencing transcriptomics white matter

项目摘要

Abstract The aged brain is thought to be more vulnerable to stresses than its young counterpart, and different in its coping with neuroinflammation and ability to repair an injury. A better understanding of the brain aging process will provide valuable information. This knowledge enables one to mitigate age-related declines in cognitive, emotional, sensory, and motor functions. Such information may also promote effective strategies for treating age-related neurodegenerative diseases, such as Alzheimer’s disease (AD). The brain is composed of multiple types of non-neuronal cells besides neurons, and each type seems to undergo unique age-related changes following its genetic program. Oligodendrocytes (OLs), a major glial cell population, form myelin sheaths, essential for rapid axonal conduction in the central nervous system (CNS). OLs also provide metabolic and nutritional support to neurons and contribute to other homeostatic regulations for axonal communication. Recently, our OL-specific transcriptomic analyses revealed that IL-33, a member of the IL-1 family known to contribute to neural circuit refining and neural repair, is increasingly expressed in OLs with age. Consequently, at one year of age, OLs become the predominant source of IL-33 (> 90% of all IL33-expressing cells) in the mouse CNS. Interestingly, IL-33 genetic variations are correlated with the risk of AD in patients, and higher levels of IL-33 in the brain significantly benefited amyloid plaque clearance in mice. Given the critical functions of IL-33, it is crucial to identify detailed cell-specific mechanisms of IL-33 in the aged brain. To understand how OL-derived IL-33 shapes brain aging and AD-like disease progression, we will employ mouse genetic tools that allow OL-specific or all CNS macroglia (OL lineage glia and astrocytes)- targeted IL-33 conditional knockout (cKO). More specifically, in Aim1, we will determine whether the loss of IL-33 expression selectively in OLs or all macroglia affects oligodendroglial integrity and regenerative features. We will also utilize single-cell transcriptomic analyses with those mice to determine how OL-derived IL-33 affects their properties and those of their neighbor cells. In Aim2, by applying the same genetic manipulations to a mouse model of AD (APP/PS1), we will determine whether OL-specific IL-33 regulates AD-like diseases and cognitive deficits, as well as microglia- mediated clearance of beta-amyloid (Ab) deposits. Finally, in Aim3, we will also overexpress IL33 in OLs or all macroglia to see if higher levels of IL33 impact OL integrity and Ab clearance. If successfully conducted, this study will advance our understanding of cell-cell interactions, especially those mediated by IL-33 in brain aging and during the progression of AD. Our results may promote the development of a therapeutic strategy with an oligodendroglia-targeted approach and identify related molecular mechanisms and targets for treating AD patients.

抽象的人们认为，老年人的大脑比年轻的大脑更容易受到压力的影响，并且在它应对神经炎症和修复损伤的能力更好地了解大脑。衰老过程将提供有价值的信息，使人们能够减轻与年龄相关的问题。此类信息也可能促进认知、情感、感觉和运动功能的下降。治疗与年龄相关的神经退行性疾病（例如阿尔茨海默病）的有效策略 (AD) 大脑除神经元外还由多种类型的非神经元细胞组成。少突胶质细胞（OL）似乎经历了独特的与年龄相关的变化，主要的神经胶质细胞群，形成髓鞘，对于中枢轴突的快速传导至关重要神经系统 (CNS) 还为神经元提供代谢和营养支持，并有助于最近，我们的 OL 特异性转录组学研究。分析表明 IL-33 是 IL-1 家族的成员，已知有助于神经回路的细化和神经修复，随着年龄的增长，在 OL 中表达越来越多，在一岁时，OL 被测试。成为小鼠 CNS 中 IL-33 的主要来源（> 90% 的表达 IL33 的细胞）。积极的是，IL-33 遗传变异与患者患 AD 的风险相关，并且较高水平的鉴于其关键功能，大脑中的 IL-33 显着有利于小鼠淀粉样斑块的清除。由于 IL-33 的存在，确定老年大脑中 IL-33 的详细细胞特异性机制至关重要。 OL 衍生的 IL-33 如何影响大脑衰老和 AD 样疾病进展，我们将采用允许 OL 特异性或所有 CNS 大胶质细胞（OL 谱系胶质细胞和星形胶质细胞）的小鼠遗传工具 - 更具体地说，在Aim1中，我们将确定是否有针对性的IL-33条件敲除。 OL 或所有大胶质细胞选择性丧失 IL-33 表达会影响少突胶质细胞的完整性和我们还将利用这些小鼠的再生特征。在 Aim2 中，确定 OL 衍生的 IL-33 如何影响其特性及其邻近细胞的特性。将相同的基因操作应用于 AD 小鼠模型 (APP/PS1)，我们将确定 OL 特异性 IL-33 是否调节 AD 样疾病和认知缺陷以及小胶质细胞最后，在 Aim3 中，我们还将过度表达 IL33。 OL 或所有大胶质细胞，看看较高水平的 IL33 是否会影响 OL 完整性和抗体清除（如果成功）。进行后，这项研究将增进我们对细胞间相互作用的理解，特别是那些 IL-33 在大脑衰老和 AD 进展过程中介导的作用我们的结果可能会促进制定针对少突胶质细胞的治疗策略并确定相关的治疗 AD 患者的分子机制和靶点。