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-猫眼课题宝

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

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

项目状态：

未结题

起止时间：

2017-07-01 至 2027-04-30

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

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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.

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