Abstract

Disrupted sleep is a major feature of Alzheimers 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) signalling cascade. Our data indicate that A{beta} can trigger a bi-directional sleep/wake switch. Alterations to the brains A{beta} oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signalling events. HIGHLIGHTSO_LIAmyloid beta oligomers can drive either sleep or wakefulness, depending on their size C_LIO_LIWakefulness driven by short amyloid beta oligomers requires binding partners Adrenergic Beta Receptor 2 and Pgrmc1 C_LIO_LILong amyloid beta oligomers drive sleep through interaction with Prion Protein C_LIO_LIThe in vivo sleep effects of amyloid beta can be pharmacologically blocked by targeting several steps of the Amyloid beta-Prion Protein signalling cascade. C_LI