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dc.contributor.authorZhu, Bangfu
dc.contributor.authorParsons, Tom
dc.contributor.authorStensen, Wenche Gunvor Berg
dc.contributor.authorSvendsen, John Sigurd Mjøen
dc.contributor.authorFugelli, Anders
dc.contributor.authorHodge, James W.L.
dc.date.accessioned2022-09-05T07:21:10Z
dc.date.available2022-09-05T07:21:10Z
dc.date.issued2022-07-19
dc.description.abstractAlzheimer’s disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-β and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-β mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-β and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-β or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-β or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.en_US
dc.identifier.citationZhu, Parsons, Stensen, Svendsen, Fugelli, Hodge. DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer’s Disease-Down Syndrome Phenotypes. Frontiers in Pharmacology. 2022en_US
dc.identifier.cristinIDFRIDAID 2041433
dc.identifier.doi10.3389/fphar.2022.881385
dc.identifier.issn1663-9812
dc.identifier.urihttps://hdl.handle.net/10037/26607
dc.language.isoengen_US
dc.publisherFrontiers Mediaen_US
dc.relation.journalFrontiers in Pharmacology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2022 The Author(s)en_US
dc.subjectVDP::Matematikk og naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448en_US
dc.subjectVDP::Mathematics and natural scienses: 400::Chemistry: 440::Pharmaceutical chemistry: 448en_US
dc.subjectVDP::Medisinske fag: 700::Klinisk medisinske fag: 750::Nevrologi: 752en_US
dc.subjectVDP::Midical sciences: 700::Clinical medical sciences: 750::Neurology: 752en_US
dc.titleDYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer’s Disease-Down Syndrome Phenotypesen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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