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，老化的大脑比年轻的大脑更容易受到压力，而在它应对神经炎症和修复受伤的能力。更好地理解大脑衰老过程将提供有价值的信息。这些知识使人们可以减轻与年龄有关的认知，情感，感觉和运动功能下降。这样的信息也可能促进治疗与年龄有关的神经退行性疾病的有效策略，例如阿尔茨海默氏病（广告）。大脑除神经元外，由多种类型的非神经元细胞组成，每种类型在其遗传程序之后，似乎会经历与年龄相关的独特变化。少突胶质细胞（OLS），一个主要的神经胶质细胞群，形成髓鞘鞘，对于中央快速轴突传导至关重要神经系统（CNS）。 OLS还为神经元提供代谢和营养支持，并有助于轴突通信的其他稳态法规。最近，我们的OL特异性转录组分析表明，IL-33是已知有助于神经回路的IL-1家族成员和神经修复，随着年龄的增长，在OL中越来越表达。因此，在一岁时，OLS 成为小鼠中枢神经系统中IL-33（> 90％表达IL33细胞的90％）的主要来源。有趣的是，IL-33遗传变异与患者的AD风险相关，较高的水平大脑中的IL-33显着受益于小鼠的淀粉样斑块清除率。给定关键功能在IL-33中，至关重要的是确定老年大脑中IL-33的详细细胞特异性机制。到了解OL衍生的IL-33如何塑造脑衰老和类似广告的疾病进展，我们将采用小鼠遗传工具允许OL特异性或所有中枢神经系统大元（OL谱系神经胶质和星形胶质细胞） - 目标IL-33条件敲除（CKO）。更具体地说，在AIM1中，我们将确定是否在OLS或所有大胶质细胞中选择性丧失IL-33表达会影响寡头完整性和再生特征。我们还将利用这些小鼠的单细胞转录组分析确定OL衍生的IL-33如何影响其特性和邻居细胞的性质。在AIM2中将相同的遗传操作应用于AD的鼠标模型（APP/PS1），我们将确定 OL特异性IL-33是否调节类似AD的疾病和认知缺陷，以及小胶质细胞 β-淀粉样蛋白（AB）沉积物的介导的清除率。最后，在AIM3中，我们还将过表达IL33 OLS或所有大胶质细胞，以查看较高水平的IL33是否影响OL的完整性和AB清除率。如果成功进行的，这项研究将提高我们对细胞 - 细胞相互作用的理解，尤其是那些由IL-33在脑老化和AD进展过程中介导。我们的结果可能会促进使用寡头胶质细胞的方法制定治疗策略，并确定相关的用于治疗AD患者的分子机制和靶标。