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

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.