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

Federico Del Gallo, Susanna Bianchi, Ilaria Bertani, Massimo Messa, Laura Colombo, Claudia Balducci, Mario Salmona, Luca Imeri, Roberto Chiesa

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e13187
JournalJournal of Sleep Research
DOIs
Publication statusE-pub ahead of print - Sep 9 2020

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