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

基本信息

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

项目摘要

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.

概括线粒体功能障碍和突触损伤是阿尔茨海默氏病（AD）的早期病理特征 - 受影响的脑1-5和衰老的大脑。 AD中的记忆障碍是脑部病理的表现，例如淀粉样蛋白β肽（Aβ）和线粒体损伤的积累。潜在的致病机制和有效修改AD疗法的疾病仍然难以捉摸。年龄是发作和 AD的进展，尤其是晚期AD。与年龄有关的代谢变化增加了发电和沉积有毒代谢产物，例如葡萄糖衍生的甲基乙醛（MG）和晚期糖基化终产物（年龄）糖酶1（GLO1）是负责消除和的键/初始酶排毒毫克以防止形成年龄。到目前为止，GLO1在Aβ诱导的作用知之甚少 AD和AD的线粒体和淀粉样病理学，神经炎症，突触和认知功能障碍链接的鼠标模型在AD和Aβ影响的大脑中。。目前尚不清楚神经元GLO1是否是线粒体之间的机械接头功能障碍和神经粉膜和突触损伤以及神经元GLO1的获得可减轻淀粉样蛋白我们假设在AD叠加的Aβ中，MG/年龄和GLO1功能受损的过多积累服务加速和夸大淀粉样病理学，导致线粒体因此，通过GLO1获得的Aβ和年龄清除可能在防止病理，突触和认知功能障碍，并减慢AD的疾病进展。作为病因内源性危险信号淀粉样蛋白和线粒体病理学。利用新型功能获得的神经元GLO1小鼠在AD小鼠模型中和多色双光子体体内成像，同时可视化令人兴奋的抑制性突触同样的神经元，我们将探索依赖GLO1的Aβ代谢和线粒体的新机制改变并解决GLO1信号传导是否受到淀粉样病理中神经元的保护或破坏性充分建立增强GLO1作为AD治疗策略的好处/陷阱。