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:
- 金额:$ 19.69万
- 依托单位:
- 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:
- 关键词:AcuteAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmino AcidsAmygdaloid structureAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorAmyloid depositionAreaBindingBiological AssayBiological MarkersBrainBrain StemCathetersCell NucleusCerebrospinal FluidCerebrumCognitiveDataDementiaDevelopmentDiseaseElderlyExcessive Daytime SleepinessFeeding behaviorsFunctional disorderFutureG-Protein-Coupled ReceptorsGenesGoalsGoldHippocampus (Brain)HomeostasisHourHumanHypersomniasHypothalamic structureImmunoprecipitationImpaired cognitionImpairmentIndividualInterventionKineticsKnock-outLabelLateralLeucineMass Spectrum AnalysisMeasuresMetabolic Clearance RateMusNarcolepsyNerve DegenerationNeuronsNeuropeptidesPathogenesisPathologyPatientsPharmaceutical PreparationsPositron-Emission TomographyPrimary InsomniaProductionProtein IsoformsProteinsRadioimmunoassayRewardsRoleSamplingSiteSleepSleep DeprivationSleep DisordersSleeplessnessSpinal PunctureStable Isotope LabelingSynapsesSystemTauopathiesTransgenic MiceWakefulnessabeta depositionagedalpha synucleinamyloid pathologyantagonistbasecognitive functioncohorthypocretinimprovedmodifiable riskorexin 1 receptororexin Aorexin Boverexpressionpolypeptideprepro-orexinprotein structurereceptorsexsleep regulationstandard measuretau Proteinstau aggregationtau-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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Brendan Patrick Lucey其他文献
Brendan Patrick Lucey的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Brendan Patrick Lucey', 18)}}的其他基金
Effect of Suvorexant on Alzheimer's Disease Biomarkers
Suvorexant 对阿尔茨海默病生物标志物的影响
- 批准号:
10584093 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Sleep Quality and Human Amlyoid-Beta Kinetics
睡眠质量和人类β淀粉样蛋白动力学
- 批准号:
9927556 - 财政年份:2016
- 资助金额:
$ 19.69万 - 项目类别:
SLEEP QUALITY AND HUMAN AMLYOID-BETA KINETICS
睡眠质量和人类淀粉样蛋白-β 动力学
- 批准号:
9934836 - 财政年份:2016
- 资助金额:
$ 19.69万 - 项目类别:
SLEEP: A POTENTIAL NOVEL MODULATOR OF ALZHEIMER'S DISEASE PATHOLOGY
睡眠:阿尔茨海默病病理学的潜在新型调节剂
- 批准号:
8755446 - 财政年份:2014
- 资助金额:
$ 19.69万 - 项目类别:
Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease
睡眠和食欲素:从临床前到轻度症状阿尔茨海默病进展的潜在标志
- 批准号:
10622500 - 财政年份:1997
- 资助金额:
$ 19.69万 - 项目类别:
Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease
睡眠和食欲素:从临床前到轻度症状阿尔茨海默病进展的潜在标志
- 批准号:
10396450 - 财政年份:1997
- 资助金额:
$ 19.69万 - 项目类别:
Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease
睡眠和食欲素:从临床前到轻度症状阿尔茨海默病进展的潜在标志
- 批准号:
9914186 - 财政年份:
- 资助金额:
$ 19.69万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 19.69万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 19.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 19.69万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 19.69万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 19.69万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 19.69万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 19.69万 - 项目类别:
Miscellaneous Programs














{{item.name}}会员




