Role of clearance of toxic metabolites in mitochondrial and tau pathology

摘要 线粒体功能障碍和突触损伤是阿尔茨海默病的早期病理特征 大脑。抢救这种伤害的潜在机制和策略仍然难以捉摸。的确有 探讨线粒体功能障碍之间可能相互作用的有限机制研究 和神经炎症及其在AD及相关突触损伤和肌张力障碍中的作用 精神障碍(ADRD)。与年龄相关的毒性代谢物积聚，如晚期糖基化终末 产物(AGEs)和甲基乙醛(MG)扰乱线粒体和突触功能障碍。因此， 清除这些有毒的代谢物对维持线粒体的完整性很重要。 乙二酸酶1(GLO1)是清除/解毒毒性代谢物MG还原的关键酶 AGEs形成。到目前为止, GLO1在tau介导的线粒体应激、tau病理、 神经毒性寡聚体tau代谢、神经炎症、突触和认知功能障碍与AD 而ADRD仍未得到开发。 目前尚不清楚循环中的AGEs代谢产物是否与 突触线粒体功能和糖基化，神经元GLO1是否是机械性连接物 线粒体功能障碍与神经炎症和突触损伤之间的关系 神经元GLO1可减轻tau病理及突触和认知功能障碍 延缓阿尔茨海默病的进展。我们假设有毒物质的持续积累 代谢产物(MG/AGEs)作为致病的内源性危险信号启动和加速 线粒体紊乱和tau病理，导致神经炎症和突触衰竭。 GLO1对AGEs代谢产物的清除可能是减少病理生理学改变的重要因素。 与年龄相关的羰基应激和线粒体病理相关的修饰。这 该提案将解决GLO1是否是 Tau诱导的突触损伤、tau病理和神经炎症，是否增强 事实证明，GLO1有助于清除tau和有毒代谢物，提高线粒体质量，并 认知功能作为AD和ADRD的治疗策略，无论循环血清和 血小板AGEs相关代谢物与脑线粒体功能障碍相关 这些有毒的代谢物可以作为危险因素/生物标记物发生和/或进展。 早期阿尔茨海默病和年龄相关性认知功能障碍。

Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the AD-affected brain. The underlying mechanisms and strategies to rescue such injury remain elusive. There is limited mechanistic study investigating the likely interplays between mitochondrial dysfunction and neuroinflammation and their contribution to synaptic damage and tauopathy in AD and related disorder (ADRD). Age-related accumulation of toxic metabolites such as advanced glycation end products (AGEs) and methylglyoxal (MG) perturbs mitochondrial and synaptic dysfunction. Thus, clearance of these toxic metabolites are important for maintaining mitochondrial integrity. Glyoxalase 1 (GLO1) is a key enzyme for scavenging/detoxifying toxic metabolite MG to reduce AGEs formation. So far, the role of GLO1 on tau-mediated mitochondrial stress, tau pathology, neurotoxic oligomer tau metabolism, neuroinflammation, synaptic and cognitive dysfunction in AD and ADRD remains unexplored. It is unclear whether circulating AGEs metabolites correlate to synaptic mitochondrial function and glycation, whether neuronal GLO1 is a mechanistic linker between mitochondrial dysfunction and neuroinflammation and synaptic injury and if gaining of neuronal GLO1 could alleviate tau pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. We hypothesize that sustained accumulation of toxic metabolites (MG/AGEs) serves as causative endogenous danger signals to initiate and accelerate mitochondrial perturbation and tau pathology, leading to neuroinflammation and synaptic failure. Clearance of AGEs metabolites by GLO1 may be important for reducing the pathophysiological modifications associated with age-related carbonyl stress and mitochondrial pathology. This proposal will address the fundamental unexplored questions of whether GLO1 is a key player in tau-induced synaptic injury, tau pathology, and neuroinflammation, whether augmentation of GLO1 proves beneficial for clearance of tau and toxic metabolites, mitochondrial quality, and cognitive function as a therapeutic strategy in AD and ADRD, whether circulating serum and platelet AGEs-related metabolites associate with cerebral mitochondrial dysfunction, and whether these toxic metabolites can serve as risk factors/biomarkers for the onset and/or progression of early AD and age-related cognitive dysfunction.