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.

摘要 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。 受影响的大脑1-5和老化的大脑。阿尔茨海默病的记忆障碍是大脑病理的一种表现，例如 淀粉样蛋白β多肽(Aβ)蓄积与线粒体损伤。潜在的致病机制和 治疗阿尔茨海默病的有效的疾病修正疗法仍然难以找到。年龄是发病和发病的强烈危险因素 阿尔茨海默病的进展，尤其是晚发性AD。与年龄相关的代谢变化增加生成和沉积 有毒代谢产物，如葡萄糖衍生的甲基乙二醛(MG)和晚期糖基化终末产物(AGEs) 乙二酸酶1(GLO1)是一种关键的/起始酶，负责清除和 解毒MG，防止AGEs的形成。到目前为止，关于Glo1在β诱导的血管紧张素转换酶中的作用还知之甚少 AD和AD患者的线粒体和淀粉样蛋白病理、神经炎症、突触和认知功能障碍 链接的小鼠模型 在AD和β感染的大脑中。 。目前尚不清楚神经元GLO1是否是线粒体之间的机械连接物 功能障碍与神经炎性和突触损伤以及神经元GLO1的获得是否可以减轻淀粉样蛋白 我们假设 AD合并Aβ时，MG/AGEs过度积聚，GLO1功能受损 加速和夸大淀粉样蛋白病理，导致线粒体 因此，通过获得β清除A GLO1和AGEs可能在预防 病理、突触和认知功能障碍，减缓阿尔茨海默病的疾病进展。 AS 致因性内源性危险信号 淀粉样蛋白和线粒体病理学。新型功能获得性神经元GLO1小鼠在AD模型中的应用 和多色双光子体内成像，同时显示兴奋性和抑制性突触 同样的神经元，我们将探索Glo1依赖的Aβ代谢和线粒体的新机制 改变和解决GLO1信号对淀粉样蛋白病理中的神经元是保护还是破坏 充分确立增强GLO1作为AD治疗策略的利弊。