Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance

Abstract

AbstractSleep-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.