Circadian Regulation of Memory During Alzheimer's Disease Pathogenesis

阿尔茨海默病发病机制中记忆的昼夜节律调节

• 批准号: 10378080
• 负责人: Geraldine J. Kress
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378080
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Behavior; Behavioral; Biological; Biological Assay; Biology; Brain; Caregiver Burden; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical; Cognition; Collection; Communication; Complex; Cues; Dementia; Disease; Disease Progression; Electrophysiology (science); Exhibits; Functional disorder; Genetic Transcription; Goals; Health; Hippocampus (Brain); Hour; Hypothalamic structure; Impaired cognition; Institutionalization; Intervention; Knock-in; Lead; Learning; Light; Lighting; Link; Measures; Mediating; Memory; Memory impairment; Methodology; Methods; Molecular; Morbidity - disease rate; Mus; Neurons; Output; Pacemakers; Pathogenesis; Pathologic; Pathology; Peripheral; Phase; Physiological; Physiological Processes; Physiology; Process; Proteins; Regulation; Reporting; Schedule; Senile Plaques; Signal Transduction; Sleep; Structure; Support System; Synapses; Synaptic plasticity; System; Techniques; Testing; Time; abeta deposition; amyloidogenesis; care costs; circadian; circadian pacemaker; circadian regulation; cognitive function; cognitive process; effective intervention; effective therapy; improved; in vivo; insight; memory consolidation; memory process; molecular clock; mouse model; neurophysiology; novel; optogenetics; pre-clinical; suprachiasmatic nucleus; synaptic function

Project Summary We propose to investigate the association between circadian system dysfunction, cognition, and Alzheimer’s disease (AD) pathogenesis. Originally, most circadian system changes were thought to be driven by the disease process. Recently, however, there is a growing realization that long-term circadian dysfunction has serious health consequences and may even precede the clinical onset of memory deficits in AD. This field is embarking on a paradigm shift that the circadian system may directly influence AD pathogenesis. Specifically, disruption of the circadian system central pacemaker, the suprachiasmatic nucleus (SCN), may contribute to the observed fragmented circadian system dysregulation in preclinical AD. The goal of this project is to test the hypothesis that poor circadian rhythms mediated by a dysfunctional central clock directly influence AD pathogenesis. The following aims will test this hypothesis: (1) examine the effects of altered SCN function on downstream hippocampal-dependent behavioral, physiological, and molecular rhythms; (2) examine the effects of chronic aberrant SCN signaling on amyloidogenic processes; (3) examine the effects of a circadian intervention on AD pathogenesis. We will combine cutting-edge in vivo optogenetic techniques with sophisticated neurophysiological measures to examine the dynamic regulation of learning and memory processes by the circadian system. Circuit-specific optogenetic manipulation of circadian system function while assaying cognitive functions represents a highly novel and methodologically unique approach. We will decipher a mechanistic link between circadian system dysregulation and cognitive decline in AD. With this project, we are well-poised to uncover new insights into the complex biological mechanisms associated with AD. Because sleep-wake and circadian disruptions are major causes of morbidity and institutionalization among AD patients, we hope that these studies may lead to effective interventions to forestall disease progression, which would also lessen caregiver burden and decrease financial care costs associated with progressing dementia.

项目概要 我们建议调查昼夜节律系统功能障碍、认​​知和 阿尔茨海默病 (AD) 的发病机制最初被认为是由昼夜节律系统变化引起的。 然而，最近人们越来越认识到长期的昼夜节律功能障碍。 具有严重的健康后果，甚至可能先于 AD 记忆缺陷的临床发作。 正在着手进行范式转变，即昼夜节律系统可能直接影响 AD 发病机制。 具体来说，昼夜节律系统中央起搏器视交叉上核（SCN）的破坏可能会导致 有助于在临床前 AD 中观察到的支离破碎的昼夜节律系统失调。 是为了检验以下假设：由功能失调的中央时钟介导的不良昼夜节律直接影响 AD 发病机制将通过以下目标来检验这一假设：(1) 检查 SCN 功能改变的影响。 下游海马依赖性行为、生理和分子节律 (2) 检查 慢性异常的 SCN 信号对淀粉样蛋白生成过程的影响；(3) 检查昼夜节律的影响； 我们将结合尖端的体内光遗传学技术来干预AD发病机制。 复杂的神经生理学措施来检查学习和记忆的动态调节 昼夜节律系统功能的电路特异性光遗传学操纵，同时。 分析认知功能代表了一种高度新颖且方法论独特的方法。 通过这个项目，我们发现了 AD 中昼夜节律失调与认知能力下降之间的机制联系。 准备好揭示与 AD 相关的复杂生物机制的新见解。 睡眠-觉醒和昼夜节律紊乱是 AD 患者发病和住院的主要原因， 我们希望这些研究能够带来有效的干预措施，以预防疾病进展，这将 还可以减轻护理人员的负担并降低与痴呆症进展相关的财务护理成本。