The Role of Immunoproteasome Function in Alzheimer's Disease and Aging

免疫蛋白酶体功能在阿尔茨海默病和衰老中的作用

基本信息

批准号：
10298389
负责人：
Natura Myeku
金额：
$ 231.85万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10298389
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid Biogenesis Cell Nucleus Cells Cleaved cell Coculture Techniques Cognition Complex Data Set Deterioration Disease Disease Progression Etiology Exhibits Feedback Gene Expression Genes Goals Hydrophobicity Immune Immune response Impairment In Vitro Inflammatory Inflammatory Response Pathway Interferon Type II Knock-in Mouse MHC Class I Genes Mass Spectrum Analysis Mediating Microfluidic Microchips Modeling Mus Nature Neurodegenerative Disorders Neuroglia Neurons Oxidative Stress Pathogenesis Pathology Pathway interactions Peptide/MHC Complex Pharmacology Play Process Proteins Proteolysis Proteome Proteomics Receptor Cell Reporting Role Seeds Senile Plaques Signaling Protein Small Nuclear RNA Stimulus Synapses T-Cell Activation Tauopathies Technology Testing Therapeutic Tissue-Specific Gene Expression Transgenic Organisms aged aging brain amyloid pathology base cell type cytokine extracellular immune function in vivo mouse model multicatalytic endopeptidase complex neuroinflammation neurotoxicity new therapeutic target novel novel therapeutics open data oxidative damage protein degradation proteomic signature tau Proteins tau aggregation transcriptome transcriptome sequencing transcriptomics

项目摘要

ABSTRACT In Alzheimer's disease (AD), decreased activity of the constitutive form of proteasomes has been reported in the regions affected by amyloid plaque load and tau accumulation. In contrast to neurons, glial cells, besides expressing constitutive proteasomes, they express at basal levels specialized type of proteasomes called the immunoproteasomes that exhibit a higher rate of protein degradation compared to constitutive proteasomes. Upon inflammatory stimuli, such as pro-inflammatory cytokines IFN-γ or under oxidative stress, the expression of the immunoproteasome subunits is increased, whereby three catalytic constitutive proteasome subunits (β5, β1, and β2) are exchanged for immunoproteasome subunits β5i, β1i, and β2i and their proteolytic activities produce a distinct set of peptides for MHC Class I receptors and T-cell activation. Because immunoproteasomes are induced during neuroinflammation (the immune response) and oxidative stress (the non-immune response) in glial cells, their pathophysiological significance in AD is debated. It remains unclear whether immunoproteasomes, as part of cytokine inflammatory responses, contribute to the etiology of the AD progression. Or whether the biogenesis of immunoproteasomes that exhibit enhanced activity compared to constitutive proteasomes is part of a compensatory mechanism in activated glial cells to overcome inflammatory signals and protein accumulation during oxidative stress. The goal of the project is to elucidate the functional diversity of immunoproteasome across the tauopathy and AD knock-in mouse models by generating crosses with double deficient immunoproteasome model (L7M1) - (Aim 1). Moreover, utilizing single-nucleus RNA-sequencing and mass spectrometry-based quantitative proteomics, we aim to identify changes at the transcriptome and the proteome levels impacted by deficient immunoproteasomes in mice - (Aim 2). Elucidating the mechanisms of the neuro-glial feedback loop and the role of glial cells in the propagation of tau across neurons is the topic of Aim 3. Understanding the true nature of immunoproteasomes in AD is vital because its proteolytic activity and its biogenesis can be exploited pharmacologically as a novel therapeutic target against AD.

抽象的据报道，在阿尔茨海默病 (AD) 中，蛋白酶体的组成型活性降低与神经元、神经胶质细胞相比，受淀粉样斑块负荷和 tau 积累影响的区域。表达组成型蛋白酶体，它们在基础水平表达特殊类型的蛋白酶体，称为与组成型蛋白酶体相比，免疫蛋白酶体具有更高的蛋白质降解率。在炎症刺激下，例如促炎细胞因子 IFN-γ 或在氧化应激下，表达免疫蛋白酶体亚基的数量增加，因此三个催化组成型蛋白酶体亚基（β5、 β1 和 β2) 被交换为免疫蛋白酶体亚基 β5i、β1i 和 β2i 及其蛋白水解活性产生一组独特的 MHC I 类受体和 T 细胞激活肽。因为免疫蛋白酶体是在神经炎症（免疫反应）和氧化过程中诱导的神经胶质细胞中的应激（非免疫反应），其在 AD 中的病理生理学意义仍然存在争议。尚不清楚免疫蛋白酶体作为细胞因子炎症反应的一部分是否有助于病因学或者与 AD 进展相比，免疫蛋白酶体的生物发生是否表现出增强的活性。组成型蛋白酶体是激活的神经胶质细胞克服的补偿机制的一部分氧化应激期间的炎症信号和蛋白质积累。该项目的目标是阐明免疫蛋白酶体在 tau 蛋白病和通过与双缺陷免疫蛋白酶体模型 (L7M1) 杂交建立 AD 敲入小鼠模型 - （目标 1）此外，利用单核 RNA 测序和基于质谱的定量分析。蛋白质组学，我们的目标是识别受缺陷影响的转录组和蛋白质组水平的变化小鼠免疫蛋白酶体 -（目标 2）。神经胶质细胞在 tau 蛋白跨神经元传播中的作用是目标 3 的主题。了解神经胶质细胞的真正本质免疫蛋白酶体在 AD 中至关重要，因为它的蛋白水解活性及其生物发生可以被利用药理学上作为 AD 的新治疗靶点。