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

技术摘要 现在人们认识到，适应性免疫系统在清除有毒的Aβ方面发挥着不可或缺的作用 来自阿尔茨海默病(AD)大脑的低聚物。这是通过T效应细胞进入大脑来实现的 通过脉络丛(CP)及其随后与驻留的小胶质细胞的相互作用。然而，T的作用是 调节性(Tregs)细胞，在清除β寡聚体中，调节T细胞抗原炎性反应 目前还在争论中。我们已经发现Treg细胞是氧化的，而TJeff细胞是糖酵解的，而AD是 与慢性线粒体氧化磷酸化(OXPHS)缺陷和线粒体增加相关 活性氧种(MRO)的产生。因此，我们假设先前存在的差异 线粒体OXPHOS和MROS的产生与阿尔茨海默病淀粉样蛋白的易感性 慢性神经细胞损伤、毒性A-β刺激所致的蓄积和认知能力下降 低聚物的形成，以及Treg对免疫功能控制的改变。 为了检验这一假设，我们提出了三个具体目标。首先，要确定 线粒体缺陷在AD中的作用，我们将经典的核DNA(NDNA)APPsWE AD转基因与 含有明确的OXPHOS缺陷(COIV421A和ND6P25L)或已建立Treg抑制功能的线粒体DNA (mtDNAB6和mtDNANZB)，并记录它们在清除Aβ斑块和恢复认知功能方面的作用 功能。其次，为了确定Treg在调节β病理和认知中的作用，我们将使用采用 弱抑制mtDNANZB Treg细胞和强抑制mtDNAB6 Treg细胞在小鼠体内的转移 APP观察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病理和认知能力下降方面，我们将使用组织特异性CRE 重组酶以1)灭活核Ant2f1基因从而减少OXPHOS或2)激活 线粒体靶向抗氧化剂mCATf1基因，从而减少Tg2576 APPswe+mtDNAB6或 MtDNANZB小鼠。 根据我们的假设，第一个特定目标被预测为证实线粒体功能障碍 与AD有因果关系，线粒体调节Treg细胞清除抗-Aβ寡聚体。这个 预测的第二个特定目的是确认β斑块中Treg线粒体功能的重要性 移走。最后一个具体目标是确认部分OXPHOS缺陷在大脑和大脑中的作用 小胶质细胞在阿尔茨海默病易感性中的作用及其在调节β斑块中的重要性 移除和认知病理学。如果这些预测成立，他们可能会建议治疗 增强线粒体功能和减少MRO可能对治疗AD有好处。

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.