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: 10605217
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605217
• 关键词: Acceleration; 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; Circadian desynchrony; Clinical; Cognition; Collection; Communication; Complex; Cues; Dementia; Disease; Disease Progression; Electrophysiology (science); Exhibits; Functional disorder; Goals; Health; Hippocampus; Hour; Hypothalamic structure; Impaired cognition; Institutionalization; Intervention; Knock-in; 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; Transcription Initiation; 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; transmission process

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.

项目摘要 我们建议调查昼夜节律功能障碍，认知和 阿尔茨海默氏病（AD）发病机理。最初，大多数昼夜节律变化被认为是驱动的 通过疾病过程。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中记忆力防御的临床发作。这个领域 正在启动循环范围，即昼夜节律系统可能直接影响AD发病机理。 具体而言，昼夜节律中央起搏器的破坏，上核（SCN）可能 在临床前AD中观察到的昼夜节律系统失调的贡献。这个项目的目标 是为了检验以下假设，即由功能失调的中间时钟介导的少昼夜节律直接影响 AD发病机理。以下目的将检验以下假设：（1）检查改变SCN功能的影响 在下游海马依赖性行为，生理和分子节律上； （2）检查 慢性异常SCN信号传导对淀粉样生成过程的影响； （3）检查昼夜节律的影响 干预AD发病机理。我们将结合尖端的体内光遗传技术 软化神经生理学措施，以检查学习和记忆的动态调节 昼夜节律系统的过程。昼夜节律功能的特定电路特异性光遗传学操纵 分析认知功能代表了一种高度新颖且在方法论上独特的方法。我们将破译 AD的昼夜节律失调与认知能力下降之间的机械联系。有了这个项目，我们 对序列化，以发现与AD相关的复杂生物学机制的新见解。因为 睡眠醒和昼夜节律破坏是AD患者发病和制度化的主要原因， 我们希望这些研究可能会导致有效的防止疾病进展的干预措施，这将 同样减少伯恩的照料者，减少与痴呆症进展相关的金融保健成本。