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ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE

神经胶质生物钟功能障碍在阿尔茨海默病发病机制中的作用

基本信息

批准号：
10611367
负责人：
Erik Steven Musiek
金额：
$ 48.45万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611367
关键词：
APP-PS1 ARNTL gene Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Astrocytes BAG3 gene Behavior Brain CHI3L1 gene Cells Chronic Circadian Dysregulation Circadian Rhythms Clock protein Confusion Data Deposition Development Disease Progression Diurnal Rhythm Environment Functional disorder Funding Gene Expression Genes Genetic Transcription Hormone secretion Hour Human Impairment Inflammation Inflammatory Response Mediating Methods Microglia Modeling Molecular Chaperones Mus Neurobehavioral Manifestations Neuroglia Neurons Pathogenesis Pathology Pathway interactions Periodicity Phagocytosis Phase Phenotype Play Process Proteins Regulation Ribosomes Role Senile Plaques Sleep Sleep disturbances System Therapeutic Transcript Translating alpha synuclein amyloid pathology brain cell cell type circadian circadian pacemaker circadian transcriptome disabling symptom in vivo insight mouse model neuroinflammation neuroprotection new therapeutic target novel pre-clinical prevent protein aggregation protein degradation response suprachiasmatic nucleus synergism tau Proteins tau aggregation transcriptome sequencing translatome

项目摘要

PROJECT SUMMARY/ABSTRACT Role of glial circadian clock dysfunction in the pathogenesis of Alzheimer’s Disease Chronic disruptions of the circadian system, manifesting as sleep disturbances, day-night confusion, and “sundowning”, are well-described and debilitating symptoms of Alzheimer’s Disease (AD). While circadian disruption has long been considered a consequence of the degenerative process in AD, accumulating human and mouse data suggest that circadian rhythm abnormalities may begin before overt cognitive symptoms, and could play an important contributory role in AD pathogenesis. Circadian rhythms are generated in cells by specific clock genes, which are expressed in neurons and glia throughout the brain and control 24-hour oscillations in transcription. These cellular clocks are synchronized to the external environment by the central clock in the suprachiasmatic nucleus in the brain. Cellular circadian clocks are particularly robust in glial cells, regulating cellular activation and inflammatory responses in both astrocytes and microglia. We have found that the circadian clock protein BMAL1 regulates astrocyte activation, neuroinflammation, and amyloid plaque deposition in mice. We have also found that amyloid plaques cause large-scale alterations in circadian transcriptional rhythms in astrocytes. Thus, we will address the bidirectional relationship between circadian clock disruption and AD-related pathology in mouse models of AD, focusing on how the central and cellular clocks regulate astrocyte responses to protein aggregation. Using novel methods to interrogate cell type- specific transcription in vivo, we will compare the effects of central vs. cellular clock disruption on circadian function in astrocytes, both in healthy brain and in a model of AD. We then evaluate the effects of central and cellular clock disruption on pathology caused by Aβ and tau, and determine specific clock-regulated pathways in astrocytes that control protein degradation and inflammation. By understanding the bidirectional relationship between circadian rhythms and astrocyte function, we hope to identify novel therapeutic targets to prevent protein aggregation and inflammation in Alzheimer’s Disease.

项目总结/摘要胶质细胞生物钟功能紊乱在阿尔茨海默病发病机制中的作用昼夜节律系统的慢性破坏，表现为睡眠障碍，昼夜混淆， “日落”是阿尔茨海默病（AD）的充分描述的和使人衰弱的症状。虽然昼夜节律长期以来，破坏一直被认为是AD中退行性过程的结果，积累了人类小鼠数据表明，昼夜节律异常可能在明显的认知症状之前开始，可能在AD发病机制中起重要作用。昼夜节律在细胞中产生，特定的时钟基因，在整个大脑的神经元和神经胶质细胞中表达，并控制24小时转录中的振荡这些细胞时钟通过中枢神经系统与外部环境同步，大脑中视交叉上核的生物钟。细胞生物钟在神经胶质细胞中特别强大，调节星形胶质细胞和小胶质细胞中的细胞活化和炎症反应。我们发现生物钟蛋白BMAL 1调节星形胶质细胞活化、神经炎症和淀粉样斑块在小鼠体内沉积。我们还发现，淀粉样蛋白斑块会导致昼夜节律的大规模改变，星形胶质细胞的转录节律。因此，我们将讨论昼夜节律之间的双向关系， AD小鼠模型中的生物钟中断和AD相关病理学，重点关注中枢和细胞生物钟调节星形胶质细胞对蛋白质聚集的反应。使用新的方法来询问细胞类型- 在体内特异性转录，我们将比较中枢与细胞时钟中断对昼夜节律的影响，在健康大脑和AD模型中，星形胶质细胞的功能。然后，我们评估中央和 Aβ和tau引起的病理学上的细胞时钟中断，并确定特定的时钟调节途径在控制蛋白质降解和炎症的星形胶质细胞中。通过理解双向关系昼夜节律和星形胶质细胞功能之间的联系，我们希望找到新的治疗靶点，蛋白质聚集和炎症在阿尔茨海默病。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer's disease.

DOI：
10.1038/s12276-020-00494-7
发表时间：
2020-08
期刊：
Experimental & molecular medicine
影响因子：
12.8
作者：
Kang SS;Ahn EH;Ye K
通讯作者：
Ye K

Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside.

DOI：
10.1172/jci154889
发表时间：
2021-10
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
E. Musiek;T. Gómez-Isla;D. Holtzman
通讯作者：
E. Musiek;T. Gómez-Isla;D. Holtzman

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.

DOI：
10.1016/j.nbd.2021.105292
发表时间：
2021-05
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Basak JM;Ferreiro A;Cohen LS;Sheehan PW;Nadarajah CJ;Kanan MF;Sukhum KV;Dantas G;Musiek ES
通讯作者：
Musiek ES

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.