Role of clearance of toxic metabolites in mitochondrial and tau pathology

有毒代谢物清除在线粒体和 tau 病理学中的作用

• 批准号: 10720370
• 负责人: Shirley ShiDu Yan
• 金额: $ 73.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720370
• 关键词: Acceleration; Advanced Glycosylation End Products; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Attenuated; Biological Markers; Blood Platelets; Brain; Cerebral cortex; Cerebrum; DLG4 gene; Data; Disease; Disease Progression; Drug Metabolic Detoxication; Enzymes; Functional disorder; Glutathione; Human; Impaired cognition; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Lactoylglutathione Lyase; Link; Mediating; Metabolism; Microglia; Mitochondria; Modeling; Modification; Mus; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Phagocytosis; Pilot Projects; Production; Protein Isoforms; Pyruvaldehyde; Regulation; Risk Factors; Role; Serum; Signal Transduction; Stress; Synapses; Synapsins; Synaptic Transmission; Synaptosomes; System; Tauopathies; Therapeutic; age related; aged; cognitive function; follow-up; glycation; human subject; in vivo; insight; loss of function; mitochondrial dysfunction; neuroinflammation; neurotoxic; new therapeutic target; novel; postsynaptic; presynaptic; respiratory protein; synaptic failure; synaptic function; synaptic pruning; tau Proteins; tau aggregation; tau mutation

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.

总结 线粒体功能障碍和突触损伤是AD患者的早期病理特征， 个脑袋潜在的机制和策略，以挽救这种伤害仍然难以捉摸。有 研究线粒体功能障碍之间可能相互作用的有限机制研究 和神经炎症及其对AD和相关疾病中突触损伤和tau蛋白病的贡献 疾病（ADRD）。与糖尿病相关的毒性代谢产物蓄积，如晚期糖基化终末 AGEs和甲基乙二醛（MG）干扰线粒体和突触功能障碍。因此，在本发明中， 这些有毒代谢物的清除对于维持线粒体的完整性是重要的。 谷胱甘肽酶1（glycoproteinase 1，GLO 1）是一种清除/解毒有毒代谢物MG的关键酶， AGEs形成。到目前为止， GLO 1在tau介导的线粒体应激，tau病理学， AD中神经毒性寡聚体tau代谢、神经炎症、突触和认知功能障碍 ADRD仍未被探索。 目前尚不清楚循环AGEs代谢物是否与 突触线粒体功能和糖基化，神经元GLO 1是否是一个机械接头 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GLO 1可以减轻tau病理和突触及认知功能障碍， 降低AD的疾病进展。我们假设持续的毒素积累 代谢物（MG/AGEs）作为致病性内源性危险信号启动和加速 线粒体扰动和tau病理，导致神经炎症和突触失败。 GLO 1清除AGEs代谢产物可能对减少病理生理学变化具有重要意义。 与年龄相关的羰基应激和线粒体病理学相关的修饰。这 该提案将解决GLO 1是否是一个关键角色的基本未探索的问题， tau蛋白诱导的突触损伤、tau蛋白病理学和神经炎症， GLO 1被证明有益于tau和毒性代谢物的清除、线粒体质量和细胞毒性。 认知功能作为AD和ADRD的治疗策略，无论是循环血清和 血小板AGEs相关代谢产物与脑线粒体功能障碍有关， 这些毒性代谢物可作为疾病发作和/或进展的危险因素/生物标志物 早期AD和与年龄相关的认知功能障碍。