Role of Adaptive Immunity in Etiology of Alzheimer’s Disease andAlzheimer’s Disease-Related Dementias

适应性免疫在阿尔茨海默病和阿尔茨海默病相关痴呆病因学中的作用

• 批准号: 10516583
• 负责人: Douglas C Wallace
• 金额: $ 85.86万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516583
• 关键词: Abeta clearance; Ablation; Accounting; Adaptive Immune System; Adoptive Cell Transfers; Adoptive Transfer; Agreement; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloidosis; Antigens; Antioxidants; Brain; Cells; Chronic; Cognition; Cognitive; Collection; DNA; DNA Sequence; Defect; Dementia; Disease; Enterobacteria phage P1 Cre recombinase; Eragrostis; Etiology; Excision; FOXP3 gene; Genes; Glycolysis; Immune; Immune system; Impaired cognition; Impairment; Inflammation; Inflammatory Response; Interferons; Leukocytes; Licensing; Mediating; Memory; Microglia; Mitochondria; Mitochondrial DNA; Mus; Neuraxis; Neurons; Nuclear; Oligopeptides; Oxidative Phosphorylation; Oxides; Pathology; Peripheral; Physiology; Play; Predisposition; Production; Public Health; Reactive Oxygen Species; Regulatory T-Lymphocyte; Reporting; Role; Senile Plaques; Structure of choroid plexus; T cell regulation; Testing; Tg2576; Tissues; Transgenes; Transgenic Mice; Variant; abeta accumulation; abeta oligomer; adaptive immunity; base; brain parenchyma; cell injury; cell type; cognitive capacity; cognitive function; conditional mutant; effector T cell; immune function; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; mutant; recruit; response; restoration

Technical Abstract It is now appreciated that the adaptive immune system plays an integral role in the removal of toxic Aβ oligomers from Alzheimer disease (AD) brains. This is accomplished through T effector cell entry into the brain via the choroid plexus (CP) and their subsequent interaction with resident microglia. However, the role of the T regulatory (Tregs) cells, which moderate Teff antigen inflammatory response, in the removal of Aβ oligomers is currently debated. We have found that Treg cells are oxidative while Teff cells are glycolytic and that AD is associated with chronic mitochondrial oxidative phosphorylation (OXPHS) defects and increased mitochondrial reactive oxygen species (mROS) production. Therefore, we hypothesize that preexisting differences in mitochondrial OXPHOS and mROS production can predispose to Alzheimer disease amyloid accumulation and cognitive decline due to chronic neuronal cell damage, stimulation of toxic Aβ oligomer formation, and alteration in the Treg control of immune function. To test this hypothesis, we propose three specific aims. First, to determine the importance of mitochondrial defects in AD, we will combine the classical nuclear DNA (nDNA) APPswe AD transgene with mtDNAs harboring defined OXPHOS defects (COIV421A and ND6P25L) or established Treg suppressive function (mtDNAB6 and mtDNANZB) and document their effects on clearance of Aβ plaques and restoration of cognitive function. Second, to determine the role of Treg in modulating Aβ pathology and cognition, we will use adoptive transfer of weakly Teff-suppressive mtDNANZB Treg cells and strongly Teff-suppressive mtDNAB6 Treg cells in APPswe mtDNAB6 or mtDNANZB mice and evaluate Aβ plaque removal and cognitive function. Lastly, to determine the effects of mitochondrial OXPHOS defects and mROS production on the central nervous system, CP, Treg cells, and microglia in terms of Aβ pathology and cognitive decline, we will use tissue-specific Cre recombinases to either 1) inactivate the nuclear Ant2fl gene thereby reducing OXPHOS or 2) activate the mitochondrially-targeted anti-oxidant mCATfl gene, thereby reducing mROS in Tg2576 APPswe + mtDNAB6 or mtDNANZB mice. According to our hypothesis, the first specific aim is predicted to confirm that mitochondrial dysfunction is causally related to AD and that mitochondria modulate the anti-Aβ oligomer removal by Treg cells. The second specific aim is predicted to confirm the importance of Treg mitochondrial function in Aβ plaque removal. The last specific aim is predicted to confirm the role of partial OXPHOS defects in the brain and microglia in predisposition to AD and to establish the importance of Treg mROS in modulating Aβ plaque removal and cognitive pathology. Should these predictions be born out, they may suggest that therapies to enhance mitochondrial function and reduce mROS may prove beneficial in treating AD.

技术摘要 现在人们认识到适应性免疫系统在清除有毒 Aβ 方面发挥着不可或缺的作用 来自阿尔茨海默病（AD）大脑的寡聚物。这是通过效应 T 细胞进入大脑来完成的 通过脉络丛（CP）及其随后与驻留小胶质细胞的相互作用。然而，T 的作用 调节 (Treg) 细胞可调节 Teff 抗原炎症反应，去除 Aβ 寡聚体 目前正在争论中。我们发现 Treg 细胞是氧化性的，而 Teff 细胞是糖酵解性的，AD 是 与慢性线粒体氧化磷酸化（OXPHS）缺陷和线粒体增加有关 活性氧（mROS）的产生。因此，我们假设先前存在的差异 线粒体 OXPHOS 和 mROS 的产生可能诱发阿尔茨海默病淀粉样蛋白 由于慢性神经元细胞损伤、有毒 Aβ 刺激而导致的积累和认知能力下降 寡聚体的形成以及 Treg 控制免疫功能的改变。 为了检验这一假设，我们提出了三个具体目标。首先，确定重要性 AD 中的线粒体缺陷，我们将经典的核 DNA (nDNA) APPswe AD 转基因与 mtDNA 含有确定的 OXPHOS 缺陷（COIV421A 和 ND6P25L）或已确定的 Treg 抑制功能 （mtDNAB6 和 mtDNANZB）并记录它们对 Aβ 斑块清除和认知恢复的影响 功能。其次，为了确定 Treg 在调节 Aβ 病理学和认知中的作用，我们将使用过继 弱 Teff 抑制性 mtDNANZB Treg 细胞和强 Teff 抑制性 mtDNAB6 Treg 细胞的转移 APPswe mtDNAB6 或 mtDNANZB 小鼠并评估 Aβ 斑块去除和认知功能。最后，为了 确定线粒体 OXPHOS 缺陷和 mROS 产生对中枢神经系统的影响， CP、Treg 细胞和小胶质细胞在 Aβ 病理学和认知能力下降方面，我们将使用组织特异性 Cre 重组酶可以 1) 灭活核 Ant2fl 基因，从而减少 OXPHOS 或 2) 激活 线粒体靶向抗氧化 mCATfl 基因，从而减少 Tg2576 APPswe + mtDNAB6 中的 mROS 或 mtDNANZB 小鼠。 根据我们的假设，预测第一个具体目标是确认线粒体功能障碍 与 AD 有因果关系，并且线粒体调节 Treg 细胞去除抗 Aβ 寡聚体。这 第二个具体目标是预测确认 Treg 线粒体功能在 Aβ 斑块中的重要性 移动。最后一个具体目标预计是确认大脑中部分 OXPHOS 缺陷的作用以及 小胶质细胞易患 AD 并确定 Treg mROS 在调节 Aβ 斑块中的重要性 去除和认知病理学。如果这些预测得到证实，他们可能会建议治疗方法 增强线粒体功能和减少 mROS 可能对治疗 AD 有益。