Day night differences in hippocampal neurophysiology in Alzheimers disease

项目摘要/摘要 目前还没有治愈阿尔茨海默氏症的方法，阿尔茨海默氏症是全球最常见的痴呆症原因，而 有限的治疗只会减缓疾病的进展。阿尔茨海默病的特征是致病的淀粉样蛋白 β(Aβ)斑块堆积、tau缠结和认知障碍。亚临床癫痫样活动或 表明网络过度兴奋的癫痫发作也存在于早期阿尔茨海默病(定义为 通过正常认知和临床前斑块病理检查)。有趣的是，癫痫样活动更强，癫痫发作 在非活动期(人类为夜间)和阿尔茨海默病患者中，阈值一般较低。这 在阿尔茨海默病患者中可能会因为记录的睡眠觉醒中断而加剧 由生物钟驱动的周期。昼夜节律是生理和生理活动中的内源性振荡。 发生在24小时内的行为。它们是由细胞转录-翻译反馈环驱动的， 涉及蛋白质BMAL1、PER1/2和CRY1/2，统称为分子时钟。昼夜节律 在健康的认知功能、网络活动(癫痫样活动和 癫痫)和蛋白质表达，包括参与突触功能的蛋白质和致病蛋白质 以β的身份。虽然这些节律在阿尔茨海默病中受到干扰，但几乎没有人做过什么工作来研究 阿尔茨海默病患者神经生理昼夜紊乱的后果以及这些紊乱是如何 可能会加重疾病的病理。已发表的文献和初步数据表明，抑制作用减弱 白天在观察到的过度兴奋和认知障碍中起作用，但几乎没有采取任何措施 海马区昼夜差异消失在认知障碍和β中的作用 病理学。这一建议旨在检验这样一种假设，即海马区白天抑制的丧失 阿尔茨海默病通过确定这一昼夜是否存在而导致认知障碍和β发病机制 在阿尔茨海默病的J20小鼠模型中，生理上的差异发生了改变，如果恢复到这个昼夜 区别是必要的，也是拯救认知障碍和β病理的充分条件。这将是 通过电生理学、化学遗传学、生化和行为分析完成。此外， 建议的实验将在我的赞助商和共同赞助商的指导下完成，这两位专家都是 生物钟和阿尔茨海默氏症，以及在理想的环境中适合 了解导致阿尔茨海默病的分子和功能缺陷。日夜揭开面纱 生理学上的差异和生理上的破坏不仅将为可能的治疗提供洞察力 目标，以及何时应该进行干预以最有效地改善阿尔茨海默病 症状或延迟病理发作。

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.