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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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