Elucidating the role of circadian-gated cognitive disruption in Alzheimer’s disease pathogenesis

项目摘要 随着65岁及以上人口比例的快速增长与寿命的增加 在预期情况下，迫切需要解决影响老年人口的疾病状况。其中之一 这些疾病--可能是最具破坏性的--是阿尔茨海默病(AD)。除了认知障碍外， 在AD的基础上，这些患者患有包括认知在内的昼夜节律系统的失调。这 计时系统对细胞水平的健康和整体生理学都是至关重要的；因此，昼夜节律的紊乱可能 对健康有深刻的负面影响，进一步加剧了AD的症状。具体来说，昼夜节律- 门控认知是内在的24小时调节循环，它是学习和记忆效率的基础 这一天。沿着这些思路，这项工作的目标是更好地了解大脑中的分子成分 它介导了AD患者昼夜节律门控认知的恶化。利用一套创新的方法 从行为测试到活体颅窗多光子成像，这项工作将解决以下具体问题 目标。到目前为止，我的论文工作(目标1)表明，昼夜节律门控认知缺陷存在于 快速淀粉样蛋白沉积的小鼠模型以及产生昼夜节律的核心时钟基因的干扰 时机可能会调解这些问题。昼夜节律调节过多的细胞过程，包括功能 丝裂原活化蛋白激酶(MAPK)通路。此外，MAPK通路对于 昼夜节律门控的认知过程及其激活在AD中被证明是被破坏的。因此，在下一阶段， 在我的工作中(F99，Aim 2)，我将测试MAPK通路激活的失调是否是机制联系 在AD模型中控制昼夜节律门控认知的中断。除了分析MAPK的中断 在AD的活性中，我会尝试将MAPK通路的活性恢复到基线，从而挽救昼夜节律门控 认知力。在完成我的论文工作后，我计划完成博士后奖学金(K00，AIM 3)我的目标是研究睡眠的遗传基础，同时研究睡眠的遗传机制 神经退行性疾病中的功能障碍。这项博士后工作将补充我的昼夜节律训练 生物学和神经退行性变最终为我提供了必要的工具和技能来解决问题 关于睡眠和昼夜节律紊乱在神经退行性疾病中的相互作用。

Project Abstract As the portion of the population that is aged 65 and older rapidly increases in parallel with increases in life expectancy, there is an urgent need to address the disease states that affect the elderly population. One of these—perhaps the most devastating—is Alzheimer’s disease (AD). In addition to the cognitive impairments that underlie AD, these patients suffer with dysregulation of their circadian timing system including cognition. This timing system is vital to health at the cellular level and to overall physiology; hence, circadian disruptions can have profound negative effects on health, further exacerbating the AD symptomology. Specifically, circadian- gated cognition is the inherent 24-hour cycles of regulation that underlie efficacy of learning and memory across the day. Along these lines, the goal of this work is to better understand the molecular components in the brain that mediate deterioration of circadian-gated cognition in AD. Utilizing an innovative set of approaches ranging from behavioral testing to in vivo cranial window multiphoton imaging, this work will address the following specific aims. My dissertation work thus far (Aim 1) has shown that circadian-gated cognitive deficits are present in a mouse model of rapid amyloid deposition and that there are disruptionin core clock genes that generate circadian timing may mediate these. Circadian timing regulates a plethora of cellular processes, including the functionality of the mitogen activated protein kinase (MAPK) pathway. Furthermore, the MAPK pathway is essential to circadian-gated cognitiveprocesses and its activation has been shown to be disrupted in AD. Thus, in next phase of my work (F99, Aim 2), I will test if the dysregulation of MAPK pathway activation is the mechanistic link governing disruption of circadian-gated cognition in a model of AD. In addition to profiling the disruption of MAPK activity in AD, I will attempt to restore activity of the MAPK pathway to baseline, thus rescuing circadian-gated cognition. Upon the completion of my dissertation work, I plan to complete a postdoctoral fellowship (K00, Aim 3) where I will aim to study the genetic basis of sleep in parallel with the genetic mechanisms underlying sleep dysfunction in neurodegenerative disorders. This postdoctoral work will complement my training in circadian biology and neurodegeneration ultimately providing me the necessary tools and skill to address questions regarding the interplay of sleep and circadian rhythmicity disruption in neurodegenerative.