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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' 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

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.

摘要 老年人的大脑被认为比年轻人的大脑更容易受到压力的影响， 应对神经炎症和修复损伤的能力。更好地了解大脑 老化过程将提供有价值的信息。这些知识使人们能够减轻与年龄有关的 认知、情感、感觉和运动功能下降。此类信息还可能促进 治疗老年性神经退行性疾病，如阿尔茨海默病的有效策略 （AD）。大脑是由多种类型的非神经元细胞除了神经元，每一种类型 似乎经历了独特的年龄相关的变化后，其遗传程序。少突胶质细胞（OL）， 一个主要的神经胶质细胞群，形成髓鞘，对中枢神经系统的快速轴突传导至关重要 神经系统（CNS）。OL还为神经元提供代谢和营养支持， 轴突通讯的其他稳态调节。最近，我们的OL特异性转录组学 分析显示，IL-33是IL-1家族的一个成员，已知有助于神经回路的改善， 和神经修复，随着年龄的增长，在OL中表达越来越多。因此，在一岁时，OL 成为小鼠CNS中IL-33的主要来源（所有IL-33表达细胞的> 90%）。 有趣的是，IL-33基因变异与患者患AD的风险相关，并且IL-33基因变异水平越高， 脑中的IL-33显著有益于小鼠中的淀粉样斑块清除。鉴于关键功能 因此，确定IL-33在老年脑中的详细细胞特异性机制至关重要。到 为了了解OL衍生的IL-33如何影响脑老化和AD样疾病的进展，我们将采用 小鼠遗传工具允许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）- 靶向IL-33条件性敲除（cKO）。更具体地说，在目标1中，我们将确定 IL-33在OL或所有大胶质细胞中选择性表达的缺失影响少突胶质细胞的完整性， 再生功能。我们还将利用这些小鼠的单细胞转录组学分析， 确定OL衍生的IL-33如何影响它们的特性及其邻近细胞的特性。在Aim 2中， 将相同的遗传操作应用于AD的小鼠模型（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， 介导的β-淀粉样蛋白（Ab）沉积物的清除。最后，在Aim 3中，我们还将过表达IL 33， OL或所有大胶质细胞，以观察较高水平的IL 33是否影响OL完整性和Ab清除。如果成功 这项研究将促进我们对细胞间相互作用的理解，特别是那些 IL-33介导的脑老化和AD的进展过程中。我们的研究结果可能会促进 开发具有少突胶质细胞靶向方法的治疗策略，并确定相关的 治疗AD患者的分子机制和靶点。