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Characterization of Orexin/Hypocretin Kinetics in Alzheimer's Disease

阿尔茨海默病中食欲素/下丘脑分泌素动力学的表征

基本信息

批准号：
10491248
负责人：
Brendan Patrick Lucey
金额：
$ 19.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491248
关键词：
Acute Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amino Acids Amygdaloid structure Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Area Binding Biological Assay Biological Markers Brain Brain Stem Catheters Cell Nucleus Cerebrospinal Fluid Cerebrum Cognitive Data Dementia Development Disease Elderly Excessive Daytime Sleepiness Feeding behaviors Functional disorder Future G-Protein-Coupled Receptors Genes Goals Gold Hippocampus (Brain)Homeostasis Hour Human Hypersomnias Hypothalamic structure Immunoprecipitation Impaired cognition Impairment Individual Intervention Kinetics Knock-out Label Lateral Leucine Mass Spectrum Analysis Measures Metabolic Clearance Rate Mus Narcolepsy Nerve Degeneration Neurons Neuropeptides Pathogenesis Pathology Patients Pharmaceutical Preparations Positron-Emission Tomography Primary Insomnia Production Protein Isoforms Proteins Radioimmunoassay Rewards Role Sampling Site Sleep Sleep Deprivation Sleep Disorders Sleeplessness Spinal Puncture Stable Isotope Labeling Synapses System Tauopathies Transgenic Mice Wakefulness abeta deposition aged alpha synuclein amyloid pathology antagonist base cognitive function cohort hypocretin improved modifiable risk orexin 1 receptor orexin A orexin B overexpression polypeptide prepro-orexin protein structure receptor sex sleep regulation standard measure tau Proteins tau aggregation tau-1

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) as insoluble plaque, tau aggregation and hyperphosphorylation, neuronal degeneration, synaptic loss, and eventual cognitive dysfunction and dementia. Soluble forms of Aβ and tau, proteins critical to Alzheimer’s disease pathogenesis, change in cerebrospinal fluid (CSF) with sleep-wake activity. CSF Aβ and tau concentrations increase during wakefulness and decrease during sleep in both mice and humans. Based on these findings, sleep is hypothesized to be a potential marker for Alzheimer’s disease pathology and/or a modifiable risk factor for Alzheimer’s disease. Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are two wake- promoting neuropeptides encoded by a common precursor polypeptide, prepro-orexin. The orexin system regulates sleep-wake activity, feeding behavior, energy homeostasis, and the reward system. Orexin deficiency causes narcolepsy, a sleep disorder resulting in excessive daytime sleepiness. Substantial evidence supports a role for the orexin system in the development of Alzheimer’s disease pathology. Knocking out the orexin gene in amyloid precursor protein (APP) transgenic mice that develop amyloid deposition led to a marked decrease in amyloid pathology in the brain. Studies in APP transgenic mice found that treatment with almorexant, a drug that blocks orexins at their receptors, decreased Aβ concentrations while administration of orexin increased them. Further, prolonged treatment with almorexant decreased amyloid deposition. In humans, CSF orexin-A also correlates with CSF Aβ, tau, phospho-tau, and alpha-synuclein concentrations in individuals with AD and other dementias. Patients with narcolepsy (i.e., with orexin deficiency) have reduced CSF Aβ, tau, phospho-tau concentrations, and amyloid deposition on amyloid PET compared to age- and sex- matched controls. These findings strongly suggest that orexin is a potential Alzheimer’s disease biomarker and that blocking orexin will modulate amyloid and potentially tau pathology in the brain. Orexin kinetics (e.g., production and clearance rates) are not understood and CSF orexin remains poorly characterized at the protein structure and isoform level. The gold standard for measuring CSF orexin-A is a radioimmunoassay. The overall goal of this proposal is to fully characterize orexin isoforms in CSF from humans with and without AD pathology using mass spectrometry in order to quantify prepro- orexin, orexin-A, orexin-B, and 13C6-leucine labeled and unlabeled orexins, and assess the utility of orexin concentrations and kinetics in quantifying AD neurodegeneration and changes in sleep-wake activity. This study will aid in identifying disease specific isoforms for future biomarker use, improve understanding of the pathophysiology of sleep disorders such as primary insomnia, narcolepsy, and other hypersomnias of central origin, as well as allow for an understanding of how the orexin system is involved in AD pathology and who may respond to a sleep intervention.

项目总结