Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of Amyloid-beta in Mice with Alzheimer's Disease Pathology

作者：Roh, Jee Hoon; Huang, Yafei; Bero, Adam W.; Kasten, Tom; Stewart, Floy R.; Bateman, Randall J.; Holtzman, David M.^*

来源：Science Translational Medicine, 2012, 4(150): 150ra122.

DOI：10.1126/scitranslmed.3004291

• MILD COGNITIVE IMPAIRMENT
• A-BETA
• INTERSTITIAL FLUID
• CIRCADIAN-RHYTHMS
• NEURONAL-ACTIVITY
• ANIMAL-MODELS
• OLDER WOMEN
• MOUSE MODEL
• IN-VIVO
• DEPOSITION

Aggregation of amyloid-beta (A beta) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before A beta aggregation, concentrations of extracellular soluble A beta in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of A beta deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in A beta change with age and A beta aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF A beta in the brain of the APPswe/PS1 delta E9 mouse model of AD before A beta plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF A beta dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid A beta in young adult humans with presenilin mutations was also markedly attenuated after A beta plaque formation. Virtual elimination of A beta deposits in the mouse brain by active immunization with A beta(42) normalized the sleep-wake cycle and the diurnal fluctuation of ISF A beta. These data suggest that A beta aggregation disrupts the sleep-wake cycle and diurnal fluctuation of A beta. Sleep-wake behavior and diurnal fluctuation of A beta in the central nervous system may be functional and biochemical indicators, respectively, of A beta-associated pathology.

• 出版日期2012-9-5