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

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.

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。这些信息还可能促进 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。考虑到 IL-33，确定IL-33在老年大脑中的详细源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IL-33条件敲除（cKO）或过表达。我们将 检查这些基因操作对老年人OL存活和髓鞘维持的影响 个脑袋此外，这些IL 33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AD样疾病和认知功能。 缺陷，以及小胶质细胞介导的β-淀粉样蛋白（Aβ）沉积物清除。相同的遗传 操作也将用于星形胶质细胞;因此，OL衍生的IL 33的相对重要性将是 与星形胶质细胞IL 33相比。 如果成功进行，这项研究将促进我们对细胞间相互作用的理解， 特别是在脑老化和AD进展期间由IL-33介导的那些。我们的研究结果可能会促进 开发一种以少突胶质细胞为靶点的治疗策略， 治疗AD患者的相关分子机制和靶点。