Sleep inhibition induced by amyloid-β oligomers is mediated by the cellular prion protein

Sleep is severely impaired in patients with Alzheimer's disease. Amyloid-β deposition in the brain of Alzheimer's disease patients is a key event in its pathogenesis and is associated with disrupted sleep, even before the appearance of cognitive decline. Because soluble amyloid-β oligomers are the key mediators of synaptic and cognitive dysfunction in Alzheimer's disease and impair long-term memory in rodents, the first aim of this study was to test the hypothesis that amyloid-β oligomers would directly impair sleep in mice. The cellular prion protein is a cell surface glycoprotein of uncertain function. Because cellular prion protein binds oligomeric amyloid-β with high affinity and mediates some of its neurotoxic effects, the second aim of the study was to test whether amyloid-β oligomer-induced sleep alterations were mediated by cellular prion protein. To address these aims, wild-type and cellular prion protein-deficient mice were given acute intracerebroventricular injections (on different days, at lights on) of vehicle and synthetic amyloid-β oligomers. Compared to vehicle, amyloid-β oligomers significantly reduced the amount of time spent in non-rapid eye movement sleep by wild-type mice during both the light and dark phases of the light–dark cycle. The amount of time spent in rapid eye movement sleep was reduced during the dark phase. Sleep was also fragmented by amyloid-β oligomers, as the number of transitions between states increased in post-injection hours 9–24. No such effects were observed in cellular prion protein-deficient mice. These results show that amyloid-β oligomers do inhibit and fragment sleep, and that these effects are mediated by cellular prion protein.