Day night differences in hippocampal neurophysiology in Alzheimers disease

项目总结/摘要 目前还没有治愈阿尔茨海默病的方法，阿尔茨海默病是全球痴呆症最普遍的原因， 有限的治疗只能减缓疾病进展。阿尔茨海默病的特征是致病性淀粉样蛋白 β（Aβ）斑块积聚、tau蛋白缠结和认知障碍。亚临床癫痫样活动或 癫痫发作，这是网络过度兴奋的指示，也存在于早期阿尔茨海默病（定义 通过正常认知和临床前斑块病理学）。有趣的是，癫痫样活动更大， 一般来说，在非活动期（人类的夜晚）和阿尔茨海默病中，阈值较低。这 在阿尔茨海默病患者中可能会加剧，因为记录显示他们的睡眠中断 周期，这是由生物钟驱动。昼夜节律是生理学中的内源性振荡， 在24小时内发生的行为。它们由细胞转录-翻译反馈环驱动， 包括蛋白质BMAL 1、PER 1/2和CRP 1/2，统称为分子钟。昼夜节律 在健康的认知功能、网络活动（癫痫样活动和 癫痫发作）和蛋白质表达，包括参与突触功能的蛋白质和致病蛋白质， Aβ。虽然这些节律在阿尔茨海默氏病中受到干扰，但很少有人研究这些节律。 阿尔茨海默病神经生理学昼夜中断的后果以及这些中断是如何发生的 可能会加剧疾病的病理学。已发表的文献和初步数据表明， 在观察到的过度兴奋和认知障碍中起作用，但几乎没有做过什么 阐明海马抑制中昼夜差异的丧失在认知障碍和Aβ中的作用 病理这项提议旨在验证海马白天抑制的丧失在海马神经元中的假设。 阿尔茨海默氏病有助于认知障碍和Aβ发病机制，通过确定这一昼夜 在阿尔茨海默病的J20小鼠模型中， 差异是必要的，足以挽救认知障碍和Aβ病理。这将是 通过电生理学、化学遗传学、生物化学和行为测定来完成。另夕h 拟议的实验将在我的赞助商和共同赞助商的指导下完成，他们都是 生物钟和阿尔茨海默病，以及在一个环境中， 了解导致阿尔茨海默病的分子和功能缺陷。揭开昼夜 生理学上的差异和生理学上的破坏不仅将提供对可能的治疗方法的了解， 目标，以及何时应该实施干预措施以最有效地改善阿尔茨海默病 症状或延迟病理性发作。

PROJECT SUMMARY/ABSTRACT There is currently no cure for Alzheimer’s disease, the most prevalent cause of dementia worldwide, and the limited treatments only slow disease progression. Alzheimer’s disease is characterized by pathogenic amyloid beta (Aβ) plaque accumulation, tau tangles, and cognitive impairment. Subclinical epileptiform activity or seizures, which are indicative of network hyperexcitability, are also present in early Alzheimer’s disease (defined by normal cognition and preclinical plaque pathology). Interestingly, epileptiform activity is greater and seizure thresholds are lower during the inactive phase (night in humans) in general and in Alzheimer’s disease. This may be exacerbated in Alzheimer’s disease patients because of documented disruptions in their sleep wake cycle, which is driven by the circadian clock. Circadian rhythms are endogenous oscillations in physiology and behavior occurring over a 24-hour period. They are driven by a cellular transcription-translation feedback loop, involving the proteins BMAL1, PER1/2, and CRY1/2, collectively known as the molecular clock. Circadian rhythm driven day-night differences are seen in healthy cognitive function, network activity (epileptiform activity and seizures), and protein expression, including proteins involved in synaptic function and pathogenic proteins such as Aβ. While these rhythms are perturbed in Alzheimer’s disease, little work has been done to investigate the consequences of day-night disruptions of neurophysiology in Alzheimer’s disease and how these disruptions might exacerbate disease pathology. Published literature and preliminary data suggest that decreased inhibition during the day plays a role in the observed hyperexcitability and cognitive impairment, but little has been done to elucidate the role of loss of day-night differences in hippocampal inhibition in cognitive impairment and Aβ pathology. This proposal aims to test the hypothesis that the loss of hippocampal day-time inhibition in Alzheimer’s disease contributes to cognitive impairment and Aβ pathogenesis by determining if this day-night difference in physiology is altered in the J20 mouse model of Alzheimer’s disease, and if restoring this day-night difference is necessary and sufficient to rescue cognitive impairment and Aβ pathology. This will be accomplished through electrophysiology, chemogenetics, biochemical, and behavioral assays. Additionally, the proposed experiments will be completed under the guidance of my sponsor and co-sponsor, both experts in circadian clocks and Alzheimer’s disease respectively, as well as in an environment ideally suited for understanding the molecular and functional deficits contributing to Alzheimer’s disease. Uncovering day-night differences in physiology and disruptions of that physiology will not only provide insight to possible therapeutic targets, but also when interventions should be administered to most effectively ameliorate Alzheimer’s disease symptoms or delay pathological onset.