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: 10053947
• 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/10053947
• 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病（AD）和大脑皮层破坏之间的明确联系。 昼夜节律计时系统然而，这种关系的机械基础还不清楚， 鉴定有趣的是，如果我们试图解构这种关系，并将其置于 随着阿尔茨海默氏病对认知的深刻影响，几个观点开始成为焦点。一是数据 迄今为止已经揭示了皮质边缘回路内的昼夜节律定时调节复杂的行为状态， 包括认知。第二，AD对这些回路的功能可塑性有显著影响。这些 观察结果提出了一个有趣的问题：AD的认知缺陷是否部分源于 皮质边缘回路的昼夜节律失调作为对这一想法的初步审查，我们 本文拟验证以下假设：AD早期至中期的认知缺陷部分是由于 皮质边缘昼夜节律计时系统的保真度的系统范围的故障。为了验证这个假设，我们 已经组装了一套创新的转基因小鼠模型和最先进的成像方法， 使我们能够在疾病进展过程中描绘和操纵昼夜节律。在目标1中， 淀粉样β肽（A β）对细胞和电路计时能力的保真度的影响将是 考察在Exp. 1A，我们将使用基于细胞培养的分析方法来测试A β寡聚体对 从SCN分离的神经元的细胞自主昼夜节律计时能力（主细胞的所在地） 生物钟）、皮质和海马体。在Exp. 1B脑切片外植体成像将用于测试 A β对基于电路的昼夜节律产生的影响。在目标2中，我们建议分析时钟定时， 在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 多光子显微镜）的时钟计时在额叶皮层和海马将被用来产生一个 细胞和系统水平的时钟相位，节奏幅度和振荡器同步的轮廓， 类AD病理学的过程。本研究将通过基于免疫荧光的时钟基因作为补充 分析（Exp. 2B）和通过转录组学分析（Exp. 2C）。在目标3中，我们将测试疾病 5XFAD模型中的进展具有时钟门控（Exp. 3A）和活动诱发的（Exp. 3B）细胞信号传导， 以及树突棘的形成。在目标4中，我们将测试皮质边缘系统的去皮质化是否 振荡器是AD的5XFAD小鼠模型中认知缺陷的基础。实现这一目标的关键是测试 时钟增强化合物PF-670462是否触发皮质-边缘振荡器的激活 人群，如果是，这种效应是否是PF-670462增强认知能力的基础。如果我们的 如果基本假设得到验证，这些数据将为新的调查路线提供重要的起点 (and潜在的新的治疗干预），旨在进一步了解机械关系 (at细胞、系统和遗传学水平）之间的关系。