Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease

被引:169
|
作者
Roh, Jee Hoon [1 ,2 ,3 ,4 ]
Jiang, Hong [1 ,2 ,3 ]
Finn, Mary Beth [1 ,2 ,3 ]
Stewart, Floy R. [1 ,2 ,3 ]
Mahan, Thomas E. [1 ,2 ,3 ]
Cirrito, John R. [1 ,2 ,3 ]
Heda, Ashish [1 ,2 ,3 ]
Snider, B. Joy [1 ,2 ,3 ]
Li, Mingjie [1 ,2 ,3 ]
Yanagisawa, Masashi [5 ]
de Lecea, Luis [6 ]
Holtzman, David M. [1 ,2 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA
[4] Univ Ulsan, Dept Neurol, Asan Med Ctr, Coll Med, Seoul 138736, South Korea
[5] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
[6] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA
来源
JOURNAL OF EXPERIMENTAL MEDICINE | 2014年 / 211卷 / 13期
基金
新加坡国家研究基金会;
关键词
IN-VIVO; BETA DEPOSITION; BRAIN; MICE; CLEARANCE; PATHOLOGY; NEURONS; FLUID;
D O I
10.1084/jem.20141788
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Age-related aggregation of amyloid-beta (A beta) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects A beta aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect A. pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of A beta pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of A. pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of A beta pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate A beta pathology in the brain.
引用
收藏
页码:2487 / 2496
页数:10
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