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

技术摘要 现在认识到适应性免疫系统在清除毒性Aβ中起着不可或缺的作用 来自阿尔茨海默病（AD）脑的寡聚体。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 调节Teff抗原炎症反应的调节细胞（Teff）在清除Aβ寡聚体中的作用是 目前正在讨论。我们已经发现Treg细胞是氧化的，而Teff细胞是糖酵解的，并且AD是糖酵解的。 与慢性线粒体氧化磷酸化（OXPHS）缺陷和增加线粒体 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的产生可使阿尔茨海默病淀粉样蛋白易感 由于慢性神经元细胞损伤、毒性Aβ刺激导致的蓄积和认知能力下降 寡聚体形成和免疫功能调节性T细胞控制的改变。 为了验证这一假设，我们提出了三个具体目标。第一，确定 我们将联合收割机将经典的核DNA（nDNA）APPswe AD转基因与 携带确定的OXPHOS缺陷（COIV 421 A和ND 6P25 L）或确定的Treg抑制功能的mtDNA （mtDNAB6和mtDNANZB），并记录其对Aβ斑块清除和认知功能恢复的影响。 功能第二，为了确定Treg在调节Aβ病理和认知中的作用，我们将使用过继性免疫荧光法。 将弱Teff抑制性mtDNANZB Treg细胞和强Teff抑制性mtDNAB6 Treg细胞转移到 APPswe mtDNAB6或mtDNANZB小鼠并评估Aβ斑块去除和认知功能。最后他们希望 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病理和认知功能下降方面的作用，我们将使用组织特异性Cre 重组酶的作用，以1）抑制细胞核Ant2fl基因从而减少OXPHOS，或2）激活 靶向抗氧化剂mCATfl基因，从而减少Tg2576 APPswe + mtDNAB6或 mtDNANZB小鼠。 根据我们的假设，第一个具体的目标是预测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A β寡聚体。的 第二个具体目标是证实Treg线粒体功能在Aβ斑块中的重要性 的拔除.预测最后一个具体目标是确认脑中部分OXPHOS缺陷的作用， 小胶质细胞在AD易感性中的作用，并确定Treg mROS在调节Aβ斑块中的重要性 移除和认知病理学。如果这些预测被证实，他们可能会建议治疗， 增强线粒体功能和减少mROS可能证明对治疗AD有益。

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.