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bioRxiv · 10.1101/2022.06.08.495312

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

Özcan, G. G.·Lim, S.·Rihel, J.
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Abstract

Amyloid precursor protein (APP) is a brain-rich, single pass transmembrane protein that is proteolytically processed into multiple products, including Amyloid-beta (A{beta}), a major driver of Alzheimers disease (AD). Although both over-expression of APP, as in mouse models used to study AD, and exogenously delivered A{beta} 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 A{beta}40 and A{beta}42 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 {gamma}-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.

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Özcan, G. G., Lim, S., Rihel, J.. 2022-06-10. Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance. https://doi.org/10.1101/2022.06.08.495312

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