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：
10736636
负责人：
Shin H Kang
金额：
$ 73.89万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736636
关键词：
1 year old APP-PS1 Abeta clearance Ablation Acute Affinity Chromatography Age Age Months 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 Astrocytes Axon Biological Response Modifiers Brain Cell Communication Cells Central Nervous System 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 Knockout Mice Knowledge Maintenance Mediating Metabolic Microglia Molecular Morphology Motor Mus Myelin Myelin Sheath Natural Source Natural regeneration Nature Neuroglia Neuroimmune Neuroimmunomodulation Neurons Nuclear Nutritional Support Oligodendroglia Organ Patients Peripheral Play Population Process Production Recovery Regulation Resolution Ribosomes Risk Role Senile Plaques Sensory Serum Source Stress System Therapeutic Time Translating abeta deposition age related age related neurodegeneration aged aging brain amyloid pathology beta amyloid pathology brain shape cell type central nervous system injury conditional knockout coping coping mechanism cytokine disease phenotype experimental study extracellular gain of function genetic manipulation injury and repair member mouse genetics mouse model mutant neural circuit neural repair neuroinflammation normal aging novel overexpression programs receptor repaired response 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 source 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 IL-33 conditional knockout (cKO) or overexpression. We will examine the effects of those genetic manipulations on OL survival and myelin maintenance in the aged brain. Moreover, these IL33-related genetic manipulations will be applied to a mouse model of AD (APP/PS1), and we will determine whether OL-derived IL-33 regulates AD-like diseases and cognitive deficits, as well as microglia-mediated clearance of beta-amyloid (Aβ) deposits. The same genetic manipulations will also be used on astrocytes; thus, the relative importance of OL-derived IL33 will be compared with astroglial IL33. If successfully conducted, this study will advance our understanding of cell-cell interactions, especially those mediated by IL-33 in brain aging and during AD progression. 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。考虑到关键功能 IL-33，至关重要的是确定老年大脑中IL-33的详细源细胞特异性机制。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，我们将采用允许OL特异性IL-33条件敲除（CKO）或过表达的小鼠遗传工具。我们将检查这些遗传操纵对老年生存和髓磷脂维持的影响脑。此外，这些与IL33相关的遗传操作将应用于AD的小鼠模型（APP/PS1），我们将确定OL衍生的IL-33是否调节类似AD的疾病和认知缺乏以及小胶质细胞介导的β-淀粉样蛋白（Aβ）沉积物的清除率。相同的遗传操纵也将用于星形胶质细胞；因此，OL衍生IL33的相对重要性是与星形胶质细胞IL33相比。如果成功进行，这项研究将提高我们对细胞 - 细胞相互作用的理解，特别是那些由IL-33在大脑衰老和AD进展过程中介导的。我们的结果可能会促进以寡头胶质靶向的方法制定治疗策略，并确定相关的分子机制和治疗AD患者的靶标。