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

• 批准号: 10300328
• 负责人: Brendan Patrick Lucey
• 金额: $ 23.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300328
• 关键词: Acute; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' 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; 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

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.

项目概要 阿尔茨海默病 (AD) 的特点是淀粉样蛋白-β (Aβ) 以不溶性斑块形式沉积、tau 蛋白聚集 以及过度磷酸化、神经元变性、突触丧失以及最终的认知功能障碍 失智。可溶形式的 Aβ 和 tau 蛋白、对阿尔茨海默病发病机制至关重要的蛋白质、 具有睡眠-觉醒活动的脑脊液（CSF）。 CSF Aβ 和 tau 浓度在 小鼠和人类在睡眠期间的觉醒和减少。根据这些发现，睡眠 假设是阿尔茨海默病病理学的潜在标志和/或可改变的危险因素 阿尔茨海默病。食欲素-A 和食欲素-B（也称为下丘脑分泌素-1 和下丘脑分泌素-2）是两种唤醒 促进由共同前体多肽前体食欲素编码的神经肽。食欲素系统 调节睡眠-觉醒活动、进食行为、能量稳态和奖励系统。食欲素 缺乏会导致发作性睡病，这是一种导致白天过度嗜睡的睡眠障碍。实质性证据 支持食欲素系统在阿尔茨海默病病理学发展中的作用。淘汰掉 淀粉样前体蛋白（APP）转基因小鼠中的食欲素基因产生淀粉样蛋白沉积，导致 大脑中淀粉样蛋白病理学显着减少。对 APP 转基因小鼠的研究发现，用 Almorexant 是一种阻断食欲素受体的药物，在服用 食欲素增加了它们。此外，长期使用阿莫司特治疗可减少淀粉样蛋白沉积。在 在人类中，CSF 食欲素-A 也与 CSF Aβ、tau、磷酸 tau 和 α-突触核蛋白浓度相关。 患有 AD 和其他痴呆症的人。发作性睡病患者（即食欲素缺乏症）的食欲下降 与年龄和性别相比，CSF Aβ、tau、磷酸 tau 浓度以及淀粉样蛋白 PET 上的淀粉样蛋白沉积 匹配的控件。这些发现强烈表明食欲素是一种潜在的阿尔茨海默病 生物标志物和阻断食欲素将调节大脑中的淀粉样蛋白和潜在的 tau 蛋白病理学。 食欲素动力学（例如，产生率和清除率）尚不清楚，脑脊液食欲素仍然很差 在蛋白质结构和亚型水平上进行表征。测量 CSF 食欲素 A 的金标准是 放射免疫测定法。该提案的总体目标是充分表征脑脊液中的食欲素亚型 使用质谱法从有或没有 AD 病理学的人类中进行检测，以量化前体 食欲素、食欲素-A、食欲素-B 和 13C6-亮氨酸标记和未标记的食欲素，并评估其效用 食欲素浓度和动力学在量化 AD 神经变性和睡眠-觉醒变化中的作用 活动。这项研究将有助于识别疾病特异性亚型，以供未来生物标志物的使用，改善 了解睡眠障碍的病理生理学，例如原发性失眠、发作性睡病和其他 中枢性嗜睡症，以及了解食欲素系统如何参与 AD 病理学以及谁可能对睡眠干预有反应。