Sleep is bi-directionally modified by amyloid beta oligomers

Disrupted sleep is a major feature of Alzheimer's disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (A beta) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which A beta affects sleep are unknown. We demonstrate in zebrafish that A beta acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short A beta oligomers induce acute wakefulness through Adrenergic receptor b2 (Adrb2) and Progesterone membrane receptor component 1 (Pgrmc1), while longer A beta forms induce sleep through a pharmacologically tractable Prion Protein (PrP) signaling cascade. Our data indicate that A beta can trigger a bi-directional sleep/ wake switch. Alterations to the brain's A beta oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signaling events.