Alzheimer's disease pathogenesis and the desynchronization of cortico-limbic circadian rhythms

阿尔茨海默病的发病机制和皮质边缘昼夜节律的不同步

• 批准号: 10221593
• 负责人: KARI RENE HOYT
• 金额: $ 69.45万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221593
• 关键词: Address; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Basic Science; Behavioral; Brain; Brain region; CREB1 gene; Cause of Death; Cell Culture Techniques; Cells; Cephalic; Circadian Dysregulation; Circadian Rhythms; Clinical; Clinical Research; Cognition; Cognitive deficits; Complement; Complex; Confocal Microscopy; Data; Dendritic Spines; Disease; Disease Progression; Elderly; Functional disorder; Gene Expression; Generations; Genes; Genetic; Goals; Hippocampus (Brain); Hour; Image; Immunofluorescence Immunologic; Individual; Intervention; Learning; MAP Kinase Gene; Modeling; Molecular; Multiphoton Fluorescence Microscopy; Mus; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Pathway interactions; Phase; Population; Prosencephalon; Reporter; Reporter Genes; Role; Series; Signal Pathway; Signal Transduction; Slice; Structure; Synaptic plasticity; System; Testing; Time; Transgenic Mice; Transgenic Organisms; Venus; Work; amyloidogenesis; base; circadian; circadian pacemaker; cortico-limbic circuits; experimental study; frontal lobe; functional plasticity; imaging modality; in vivo; innovation; mouse model; multiphoton microscopy; novel therapeutic intervention; overexpression; relating to nervous system; research study; suprachiasmatic nucleus; therapy design; transcriptomics

Recent work has established a clear connection between Alzheimer’s disease (AD) and the disruption of the circadian timing system. However, the mechanistic underpinnings of this relationship have not been clearly identified. Interestingly, if we attempt to deconstruct this relationship and place it within the context of the profound effects that Alzheimer’s disease has on cognition, several ideas begin to come into focus. First, data to date has revealed that circadian timing within cortico-limbic circuits modulates complex behavioral states, including cognition. Second, AD has marked effects on functional plasticity of these same circuits. These observations raise an interesting question: could the cognitive deficits in AD result, in part, from the dysregulation of circadian timing within cortico-limbic circuits? As an initial examination of this idea, we propose to test the following hypothesis: The cognitive deficits during early- to mid-stage of AD results in part from a systems-wide breakdown in the fidelity of the cortico-limbic circadian timing systems. To test this hypothesis, we have assembled an innovative set of transgenic mouse models and state-of-the-art imaging methods that will allow us to both profile and manipulate circadian timing over the course of disease progression. In Aim 1, the effects of amyloid β peptide (Aβ) on the fidelity of cellular-and circuit-based time-keeping capacity will be examined. In Exp. 1A, we will use a cell-culture based profiling approach to test the effects of Aβ oligomer on the cell autonomous circadian timekeeping capacity of neurons isolated from the SCN (the locus of the master circadian clock), the cortex and the hippocampus. In Exp. 1B brain slice explant imaging will be used to test the effects of Aβ on circuit-based circadian rhythm generation. In Aim 2 we propose to profile clock timing and clock-gated gene expression in the 5XFAD mouse model of AD. In Exp. 2A, cranial window imaging (via multiphoton microscopy) of clock timing in the frontal cortex and the hippocampus will be used to generate a cellular- and systems-level profile of clock phasing, rhythm amplitude and oscillator synchrony over the course of the AD-like pathology. This study will be complemented by immunofluorescence-based clock gene profiling (Exp. 2B) and by transcriptomic profiling (Exp. 2C). In Aim 3, we will test the effects that disease progression in the 5XFAD model has on clock-gated (Exp. 3A) and activity-evoked (Exp. 3B) cellular signaling, as well as on dendritic spine formation. In Aim 4 we will test whether the desynchronization of cortico-limbic oscillators underlies the cognitive deficits in the 5XFAD mouse model of AD. Key to this aim will be to test whether the clock enhancing compound PF-670462 triggers the resynchronization of cortico-limbic oscillator populations, and if so, whether this effect underlies the capacity of PF-670462 to augment cognition. If our underlying hypothesis is validated, these data will provide an important starting point for new lines of inquiry (and potentially new therapeutic interventions) designed to further understand the mechanistic relationships (at a cellular, systems, and genetics level) between circadian timing and AD pathogenesis.

最近的工作已经建立了阿尔茨海默氏病（AD）与破坏之间的明显联系 昼夜节律定时系统。但是，这种关系的机械基础尚不清楚 有趣的是，如果我们试图解构这种关系并将其置于 阿尔茨海默氏病对认知的深远影响，一些想法开始焦点。首先，数据 迄今 包括认知。其次，AD对这些相同电路的功能可塑性具有明显的影响。这些 观察提出了一个有趣的问题：认知能否在广告结果中部分定义 Cortico-limbic圆圈内昼夜节律的失调？作为对这个想法的初步研究，我们 提出检验以下假设的提议：AD早期至中期期间的认知缺陷部分是由 Cortico-limbic昼夜节律定时系统的保真度范围内的范围崩溃。为了检验这一假设，我们 已经组装了一组创新的转基因鼠标模型和最先进的成像方法 允许我们在疾病进展过程中同时概况并操纵昼夜节律时机。在AIM 1中 淀粉样蛋白β肽（Aβ）对基于电路和电路的时间保存能力的保真度的影响将是 检查。在Exp。 1a，我们将使用基于细胞培养的分析方法来测试Aβ低聚物对 从SCN隔离的神经元的细胞自主昼夜节律计时能力（主的轨迹 昼夜节律时钟），皮层和海马。在Exp。 1B脑切片外植体成像将用于测试 Aβ对基于电路的昼夜节律产生的影响。在AIM 2中，我们建议介绍时钟的时钟和 AD的5xFAD小鼠模型中的时钟门控基因表达。在Exp。 2a，颅窗成像（通过 额叶皮层和海马中时钟定时的多光子显微镜）将用于生成一个 时钟相位，节奏放大器和振荡器同步的蜂窝和系统级别的轮廓 类似广告的病理学的过程。这项研究将通过基于免疫荧光的时钟基因完成 分析（exp。2b）和转录组分析（经验2C）。在AIM 3中，我们将测试疾病的影响 5xFAD模型的进展具有时钟门控（Exp。3a）和活动引起的（Exp。3b）的细胞信号传导， 以及树突状脊柱形成。在AIM 4中，我们将测试Cortico-Limbic的不同步 振荡器是AD的5xFAD小鼠模型中的认知定义的基础。这个目标的关键将是测试 时钟是否增强复合PF-670462是否触发Cortico-Limbic振荡器的重新同步 人口，如果是这样，这种影响是否是PF-670462增强认知能力的能力的基础。如果我们 基本假设已验证，这些数据将为新的查询线提供重要的起点 （并且可能是新的治疗干预措施）旨在进一步了解机械关系 （在细胞，系统和遗传学水平上）在昼夜节律和AD发病机理之间。