Sleep is bi-directionally modified by amyloid beta oligomers

SUMMARY 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 (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affects sleep are unknown. We demonstrate in zebrafish that Aβ acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short Aβ oligomers induce acute wakefulness through Adrenergic receptor b2 (Adrb2) and Progesterone membrane receptor component 1 (Pgrmc1), while longer Aβ forms induce sleep through a pharmacologically tractable Prion Protein (PrP) signalling cascade. Our data indicate that Aβ can trigger a bi-directional sleep/wake switch. Alterations to the brain’s Aβ oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signalling events. HIGHLIGHTS Amyloid beta oligomers can drive either sleep or wakefulness, depending on their size Wakefulness driven by short amyloid beta oligomers requires binding partners Adrenergic Beta Receptor 2 and Pgrmc1 Long amyloid beta oligomers drive sleep through interaction with Prion Protein The in vivo sleep effects of amyloid beta can be pharmacologically blocked by targeting several steps of the Amyloid beta-Prion Protein signalling cascade.