Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance
Summary: 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 disease (AD). Although both overexpression of APP and exogenously delivered Aβ lead to change...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224000919 |
| _version_ | 1797342179253813248 |
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| author | Güliz Gürel Özcan Sumi Lim Thomas Canning Lavitasha Tirathdas Joshua Donnelly Tanushree Kundu Jason Rihel |
| author_facet | Güliz Gürel Özcan Sumi Lim Thomas Canning Lavitasha Tirathdas Joshua Donnelly Tanushree Kundu Jason Rihel |
| author_sort | Güliz Gürel Özcan |
| collection | DOAJ |
| description | Summary: 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 disease (AD). Although both overexpression of APP and exogenously delivered Aβ lead to changes in sleep, 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, whereas larvae that lacked appb had shortened sleep bout durations at night. Treatment with the γ-secretase inhibitor DAPT also shortened night sleep bouts, whereas the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Intraventricular injection of P3 also shortened night sleep bouts, suggesting that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish. |
| first_indexed | 2024-03-08T10:29:32Z |
| format | Article |
| id | doaj.art-7ee08a28fe0147358c2e4d01951b38c9 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T10:29:32Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-7ee08a28fe0147358c2e4d01951b38c92024-01-27T06:55:49ZengElsevieriScience2589-00422024-02-01272108870Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenanceGüliz Gürel Özcan0Sumi Lim1Thomas Canning2Lavitasha Tirathdas3Joshua Donnelly4Tanushree Kundu5Jason Rihel6Department of Cell and Developmental Biology, University College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UKDepartment of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UK; Corresponding authorSummary: 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 disease (AD). Although both overexpression of APP and exogenously delivered Aβ lead to changes in sleep, 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, whereas larvae that lacked appb had shortened sleep bout durations at night. Treatment with the γ-secretase inhibitor DAPT also shortened night sleep bouts, whereas the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Intraventricular injection of P3 also shortened night sleep bouts, suggesting that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish.http://www.sciencedirect.com/science/article/pii/S2589004224000919Biological sciencesMolecular geneticsMolecular neuroscience |
| spellingShingle | Güliz Gürel Özcan Sumi Lim Thomas Canning Lavitasha Tirathdas Joshua Donnelly Tanushree Kundu Jason Rihel Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance iScience Biological sciences Molecular genetics Molecular neuroscience |
| title | Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| title_full | Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| title_fullStr | Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| title_full_unstemmed | Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| title_short | Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| title_sort | genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance |
| topic | Biological sciences Molecular genetics Molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224000919 |
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