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

摘要 在阿尔茨海默氏病（AD）中，已经报道了组成型蛋白酶体的活性降低， 受淀粉样斑块负荷和tau积累影响的区域。与神经元相反，神经胶质细胞除了 表达组成型蛋白酶体，它们在基础水平表达被称为 与组成型蛋白酶体相比，免疫蛋白酶体表现出更高的蛋白质降解速率。 在炎性刺激，如促炎细胞因子IFN-γ或氧化应激下， 免疫蛋白酶体亚单位的数量增加，由此三个催化组成型蛋白酶体亚单位（β5， β1和β2）被交换为免疫蛋白酶体亚基β5i、β 1 i和β 2 i， 产生一组独特的肽用于MHC I类受体和T细胞活化。 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， 由于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存在争议。它仍然是 免疫蛋白酶体作为细胞因子炎症反应的一部分， AD进展。或者，与其他生物相比， 组成性蛋白酶体是激活的神经胶质细胞代偿机制的一部分， 炎症信号和氧化应激过程中的蛋白质积累。 该项目的目标是阐明免疫蛋白酶体在tau蛋白病中的功能多样性， 通过与双缺陷免疫蛋白酶体模型（L7 M1）产生杂交的AD敲入小鼠模型- (Aim 1）。此外，利用单核RNA测序和基于质谱的定量 蛋白质组学，我们的目标是确定转录组和蛋白质组水平的变化，这些变化受到缺陷的影响 目的2.阐明神经胶质细胞反馈环的机制， 神经胶质细胞在tau跨神经元传播中的作用是Aim 3的主题。了解真正的本质 免疫蛋白酶体在AD中是至关重要的，因为它的蛋白水解活性和它的生物起源可以被利用， 作为抗AD的新的治疗靶点。

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.