Abstract
Amyloid precursor protein (APP) is a brain-rich, single pass transmembrane protein that is proteolytically processed into multiple products, including Amyloid-beta (Aβ), a major driver of Alzheimer’s disease (AD). Although both over-expression of APP, as in mouse models used to study AD, and exogenously delivered Aβ lead to changes in sleep behaviors, whether APP processing plays an endogenous role in regulating sleep is unknown. Here, we demonstrate that APP processing into Aβ40 and Aβ42 is conserved in zebrafish and then describe sleep/wake phenotypes in loss of function appa and appb mutants. Larvae with mutations in appa had reduced waking activity but normal sleep patterns, while larvae that lacked appb had shortened sleep bout durations at night. Treatment with the γ-secretase inhibitor DAPT also shortened sleep bouts at night, while the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Since both drugs fail to further alter sleep in appb mutants, and intraventricular injection of the App cleavage product P3 also shortens night-time sleep bouts, we conclude that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This manuscript now shows, we believe for the first time, measurements for the production of Amyloid beta 40 and 42 in zebrafish. We also show more extensive expression patterns for appa and appb. We have added new data on the effect of Bace-1 inhibitors in addition to gamma-secretase inhibitors. We also show that P3 can directly alter sleep/wake behaviors in zebrafish larvae. New Figure 1, Figure 4, Figure 5, Figure 6.