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Sleep-wake disturbances are among the earliest symptoms of Alzheimer’s disease (AD) and contribute to disease severity. Since a major driver of AD—the accumulation of amyloid-beta (Aβ) in the brain—is modulated by sleep, a “vicious” feedforward cycle has been proposed in which Aβ buildup disrupts sleep, leading to more Aβ secretion and further worsening of sleep and AD. Consistent with this idea, mouse models of AD develop early sleep phenotypes, and sleep is acutely modulated by exogenous Aβ. However, these overexpression paradigms leave unclear whether endogenous Aβ signaling contributes to sleep regulation. To tackle this question, we generated loss of function mutations in the zebrafish orthologs of Amyloid Precursor Protein (APP) and monitored larval sleep behavior. Larvae with mutations in appa had reduced waking activity levels but normal sleep patterns, while larvae that lacked appb had reduced sleep due to an inability to maintain sleep bout durations. In addition, larvae exposed to the γ-secretase inhibitor DAPT, which inhibits Aβ production from APP, also have shorter sleep bouts at night. Although γ- secretase inhibition impacts the proteolytic cleavage of many proteins, appb mutants were insensitive to the sleep bout shortening effects of DAPT, suggesting that loss of γ-secretase dependent proteolytic cleavage products of Appb are responsible for the reduced sleep maintenance phenotypes. These results are consistent with a model in which endogenous Aβ directly modulates sleep in zebrafish and supports the idea that sleep disturbances may be a useful early-onset biomarker for AD.

SUMMARYDisrupted 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.HIGHLIGHTSAmyloid beta oligomers can drive either sleep or wakefulness, depending on their sizeWakefulness driven by short amyloid beta oligomers requires binding partners Adrenergic Beta Receptor 2 and Pgrmc1Long amyloid beta oligomers drive sleep through interaction with Prion ProteinThe in vivo sleep effects of amyloid beta can be pharmacologically blocked by targeting several steps of the Amyloid beta-Prion Protein signalling cascade.

Summary Sleep is under homeostatic control, but the mechanisms that sense sleep need and correct sleep deficits remain unknown. Here, we report that sleep-promoting neurons with projections to the dorsal fan-shaped body (FB) form the output arm of Drosophila’s sleep homeostat. Homeostatic sleep control requires the Rho-GTPase-activating protein encoded by the crossveinless-c (cv-c) gene in order to transduce sleep pressure into increased electrical excitability of dorsal FB neurons. cv-c mutants exhibit decreased sleep time, diminished sleep rebound, and memory deficits comparable to those after sleep loss. Targeted ablation and rescue of Cv-c in sleep-control neurons of the dorsal FB impair and restore, respectively, normal sleep patterns. Sleep deprivation increases the excitability of dorsal FB neurons, but this homeostatic adjustment is disrupted in short-sleeping cv-c mutants. Sleep pressure thus shifts the input-output function of sleep-promoting neurons toward heightened activity by modulating ion channel function in a mechanism dependent on Cv-c., Highlights • Neurons in the dorsal fan-shaped body convey the output of the sleep homeostat • Sleep need increases the electrical excitability of these sleep-control neurons • Sleep homeostasis requires the Rho-GAP encoded by the crossveinless-c gene • Cv-c modulates ion channel function in sleep-control neurons, Donlea et al. discover mutant flies with a broken sleep homeostat: after an all-nighter, these flies are unable to correct the accumulated sleep deficit. The mutation affects a Rho-GTPase-activating protein that regulates the electrical excitability of sleep-promoting neurons.