Apolipoprotein E4-related Electrophysiological and Metabolic Impairments in Aging and Alzheimer's Disease

衰老和阿尔茨海默病中载脂蛋白 E4 相关的电生理和代谢损伤

基本信息

批准号：
10532732
负责人：
Misha Yuri Zilberter
金额：
$ 65.57万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532732
关键词：
Advanced Development Age Age Months Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Apolipoproteins Biological Markers Brain Cells Cessation of life Clinical Research Cognition Cognitive deficits Data Dementia Diagnosis Dose Electrophysiology (science)Energy Metabolism Epilepsy Event Female Functional disorder Genes Glucose Hippocampus Image Impairment Interneurons Knock-in Mouse Late Onset Alzheimer Disease Learning Longitudinal Studies Memory Memory impairment Metabolic Mitochondria Mus Nature Neurons Outcome Oxidative Stress Pathogenesis Pathology Populations at Risk Predisposition Prevention strategy Process Production Protein Isoforms Publications Publishing Reactive Oxygen Species Research Respiration Risk Factors Role Seizures Severities Slice Stress Synapses Work abeta toxicity age effect age related aging brain apolipoprotein E-3 apolipoprotein E-4 cell type cognitive process excitatory neuron genetic risk factor inhibitory neuron insulin signaling neuronal excitability pathological aging postsynaptic synaptic function therapy development

项目摘要

PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer's disease (AD) pose unique challenges for mechanistic studies and developing therapies. Age is the major risk factor for AD, and imaging and biomarker data suggest that the pathophysiological processes of AD begin more than a decade before dementia is diagnosed. Apolipoprotein (apo) E4, the major genetic risk factor for AD, lowers the age of onset in a gene dose–dependent manner. In most clinical studies, apoE4 carriers account for 60–75% of AD cases, highlighting the importance of apoE4 in AD pathogenesis. Longitudinal studies show that apoE4's detrimental effect on cognition depends on age and occurs before typical signs of AD arise. A challenge in AD research is to fully understand how risk factors, including apoE4 and age-related prodromal processes, interact to contribute to AD pathophysiology. This proposal is based on intriguing preliminary findings. First, in brain hippocampal slices, intrinsic gamma oscillations are impaired in apoE4 knock-in (KI) mice at 7 months of age, indicating impaired local network function. Second, apoE4 expression disrupts mitochondrial respiration and increases production of reactive oxygen species, likely resulting in oxidative stress and neuronal ATP depletion. Third, neuronal hypometabolism self-perpetuates, causing network alterations such as hyperexcitability responsible for increased seizure susceptibility of apoE4-KI mice and rendering the brain especially vulnerable to additional stresses induced by AD-associated amyloid-beta (Aβ) peptide, the production of which is known to be increased under metabolic crises. In addition, recent publications from my collaborator lab show that expression of apoE4 in female mice causes age-dependent impairment of GABAergic interneurons in the hippocampus, and that this impairment is associated with reduced slow gamma activity and correlates with the severity of learning and memory deficits. Understanding the mechanisms behind age-dependent apoE4 disruption of network function and the underlying metabolic pathology will help advance the preventative strategies for people at risk for AD. This proposal aims (1) to determine the effect of aging on apoE4 disruption of hippocampal network function and its relationship with GABAergic interneuron impairment, (2) investigate cell-specific effects of aging on apoE4-induced alterations in neuronal energy metabolism and their effects on network function, and (3) determine the age-dependent effects of apoE4 on cell type-specific susceptibility to Aβ toxicity. The outcomes of the proposed study will shed light on primary mechanisms of apoE4-induced pathological aging and dementia, as well as on synergistic effects of apoE4 with other AD-related factors that contribute to pathogenesis of late- onset AD.

项目摘要阿尔茨海默氏病（AD）的复杂性和多因素性质为机械带来了独特的挑战研究和发展疗法。年龄是AD的主要危险因素，成像和生物标志物数据表明在诊断出痴呆症之前，AD的病理生理过程开始了十多年。载脂蛋白（APO）E4是AD的主要遗传危险因素，降低了基因剂量依赖性的发作年龄方式。在大多数临床研究中，APOE4载体占AD病例的60-75％，强调了 AD发病机理中的APOE4。纵向研究表明，APOE4对认知的有害影响取决于年龄和发生在典型的AD出现之前。广告研究中的挑战是充分了解风险如何包括APOE4和与年龄相关的前驱过程在内的因素相互作用以促进AD病理生理学。该建议基于有趣的初步发现。首先，在脑海马切片中，固有的伽玛 7个月大的APOE4敲入（Ki）小鼠中振荡受损，表明本地网络受损功能。其次，APOE4表达会破坏线粒体呼吸并增加反应性的产生氧气，可能导致氧化物胁迫和神经元ATP耗竭。第三，神经元低代谢自我延续，导致网络变化，例如过度兴奋性，导致癫痫发作增加 APOE4-KI小鼠的敏感性，并使大脑特别容易受到由其他压力的影响广告相关的淀粉样蛋白β（Aβ）胡椒危机。此外，我的合作者实验室的最新出版物表明，雌性老鼠中APOE4的表达导致海马中GABA能中间神经元的年龄依赖性损害，并且这种障碍是与慢速伽马活性的减少相关，并且与学习和记忆缺陷的严重程度相关。了解与年龄依赖性APOE4的机制4中断网络函数和基础的机制代谢病理学将有助于推进有风险的AD风险的人们的预防策略。该建议旨在（1）确定衰老对海马网络功能的APOE4破坏的影响及其与GABA能中神经元损伤的关系，（2）研究衰老对细胞特异性影响 APOE4诱导的神经元能量代谢及其对网络功能的影响的改变，（3）确定APOE4对细胞类型特异性Aβ毒性敏感性的依赖性影响。结果在拟议的研究中，将阐明APOE4诱导的病理衰老和痴呆的主要机制，以及APOE4与其他与AD相关因素的协同作用，这些因素有助于后期的发病机理发作广告。