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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

基本信息

批准号：
10612391
负责人：
KARI RENE HOYT
金额：
$ 71.98万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10612391
关键词：
Affect Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos 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 Hour Image Immunofluorescence Immunologic Individual Intervention Learning MAP Kinase Gene Modeling Molecular Multiphoton Fluorescence Microscopy Mus Neurodegenerative Disorders Neurons Pathogenesis Pathology Pathway interactions Persons Phase Population Prosencephalon Reporter Reporter Genes Role Series Signal Pathway Signal Transduction Slice Structure Synaptic plasticity System Testing Transgenic Mice Transgenic Organisms Venus Work abeta oligomer amyloidogenesis circadian circadian pacemaker cortico-limbic circuits design experimental study frontal lobe functional plasticity imaging modality in vivo innovation mouse model multiphoton microscopy neural novel therapeutic intervention overexpression research study suprachiasmatic nucleus transcriptomic profiling

项目摘要

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.

最近的研究已经确立了阿尔茨海默病（AD）与大脑中神经系统紊乱之间的明确联系

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ribosomal S6 Kinase Regulates the Timing and Entrainment of the Mammalian Circadian Clock Located in the Suprachiasmatic Nucleus.

核糖体 S6 激酶调节位于视交叉上核的哺乳动物昼夜节律时钟的时间和夹带。

DOI：
10.1016/j.neuroscience.2023.02.003
发表时间：
2023
期刊：
Neuroscience
影响因子：
3.3
作者：
Hoyt,KariR;Li,Aiqing;Yoon,Hyojung;Weisenseel,Zachary;Watkins,Jacob;Fischer,Alex;Obrietan,Karl
通讯作者：
Obrietan,Karl

Light-induced changes in the suprachiasmatic nucleus transcriptome regulated by the ERK/MAPK pathway.