GLO1/Aβ-mediated mitochondrial and synaptic injury in Alzheimer's disease

GLO1/Aβ 介导的阿尔茨海默病线粒体和突触损伤

• 批准号: 10639086
• 负责人: Jaichandar Subramanian
• 金额: $ 239.75万
• 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: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639086
• 关键词: Abeta clearance; Acceleration; Address; Advanced Glycosylation End Products; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloidosis; Attenuated; Behavioral; Brain; Brain Pathology; Cerebrum; Color; DLG4 gene; Deposition; Disease; Disease Progression; Drug Metabolic Detoxication; Enzymes; Equilibrium; Excitatory Synapse; Exhibits; Functional disorder; Generations; Genetic Predisposition to Disease; Glucose; Hippocampus; Human; Hyperactivity; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhibitory Synapse; Injury; Innate Immune Response; Lactoylglutathione Lyase; Late Onset Alzheimer Disease; Link; Mediating; Memory; Memory impairment; Metabolic; Mitochondria; Mus; Neuronal Plasticity; Neurons; Outcome; Pathogenicity; Pathologic; Pathology; Peptide Metabolism; Phagocytosis; Pilot Projects; Production; Pyruvaldehyde; Regulation; Risk Factors; Role; Seizures; Senile Plaques; Signal Transduction; Stress; Synapses; Synapsins; Synaptic Transmission; Synaptosomes; Testing; Therapeutic; Therapeutic Agents; Visual; Visual Cortex; Visualization; abeta accumulation; age related; aging brain; amyloid pathology; familial Alzheimer disease; follow-up; gain of function; glycation; improved; in vivo; in vivo two-photon imaging; memory recognition; mitochondrial dysfunction; mouse model; neuroinflammation; neuronal excitability; novel; novel therapeutics; postsynaptic; presynaptic; prevent; synaptic failure; synaptic function; synaptic pruning; trafficking

Summary Mitochondrial dysfunction and synaptic damage are early pathological features of Alzheimer’s disease (AD)- affected brain1-5 and aging brains. Memory impairment in AD is a manifestation of brain pathologies such as accumulation of amyloid-β peptide (Aβ) and mitochondrial damage. The underlying pathogenic mechanisms and effective disease modifying therapies for AD remain elusive. Age is a strong risk factor for the onset and progression of AD, particularly late-onset AD. Age-related metabolic changes increase generation and deposition of toxic metabolites such as glucose-derived methylglyoxal (MG) and advanced glycation endproducts (AGEs) Glyoxalase 1 (GLO1) is a key/initial enzyme responsible for eliminating and detoxifying MG to prevent the formation of AGEs. So far, little is known about the role of GLO1 on Aβ-induced mitochondrial and amyloid pathology, neuroinflammation, synaptic and cognitive dysfunction in AD and AD- linked mouse models in AD- and Aβ-affected brain. . It is unclear whether neuronal GLO1 is mechanistic linker between mitochondrial dysfunction and neuroinflammaton and synaptic injury and if gain of neuronal GLO1 could alleviate amyloid We hypothesize that in AD superimposed Aβ, excessive accumulation of MG/AGEs and impaired GLO1 function serve to accelerate and exaggerate amyloid pathology, leading to mitochondrial and synaptic stress, thus, clearance of Aβ and AGEs by gain of GLO1 may be of importance in preventing pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. as causative endogenous danger signals amyloid and mitochondrial pathology. Utilizing novel gain-of-function neuronal GLO1 mice in AD mouse model and multi-color two-photon in vivo imaging to simultaneously visualize excitatory and inhibitory synapses in the same neurons, we will explore new mechanism underlying GLO1-dependent Aβ metabolism and mitochondrial alterations and address whether GLO1 signaling is protective or destructive to neurons in amyloid pathology to fully establish the benefits/pitfalls of enhancing GLO1 as a therapeutic strategy in AD.

总结 线粒体功能障碍和突触损伤是阿尔茨海默病（AD）的早期病理特征， 影响大脑1 -5和老化的大脑。AD中的记忆障碍是脑病理学的表现， 淀粉样β肽（Aβ）蓄积和线粒体损伤。潜在的致病机制和 AD的有效疾病改善疗法仍然难以捉摸。年龄是发病的一个重要危险因素， AD的进展，特别是晚发性AD。与代谢相关的代谢变化增加了生成和沉积 毒性代谢产物，如葡萄糖衍生的甲基乙二醛（MG）和晚期糖基化终产物（AGEs） Glycoprotein酶1（GLO 1）是一种关键的/初始的酶，负责消除和 解毒MG，防止AGEs的形成。到目前为止，关于GLO 1在Aβ诱导的细胞凋亡中的作用还知之甚少。 线粒体和淀粉样病变，神经炎症，突触和认知功能障碍，AD和AD- 连锁小鼠模型 在AD和Aβ影响的大脑中。 .目前尚不清楚神经元GLO 1是否是线粒体间的机械连接子， 功能障碍、神经炎性反应、突触损伤及神经元GLO 1的增加可减轻淀粉样变 我们假设 在AD合并Aβ时，MG/AGEs过度蓄积和GLO 1功能受损 加速和加重淀粉样病变，导致线粒体 和突触应激，因此，通过获得GLO 1清除Aβ和AGEs可能在预防 病理学和突触和认知功能障碍，并减缓AD的疾病进展。 作为 致因性内源性危险信号 淀粉样蛋白和线粒体病理学。在AD小鼠模型中使用新型功能获得性神经元GLO 1小鼠 和多色双光子体内成像，以同时可视化神经元中的兴奋性和抑制性突触。 同样的神经元，我们将探索新的机制，GLO 1依赖的Aβ代谢和线粒体 改变，并解决GLO 1信号传导是否是保护性或破坏性的神经元在淀粉样病变， 充分确定增强GLO 1作为AD治疗策略的益处/缺陷。