AUTHOR=Zhu Bangfu , Parsons Tom , Stensen Wenche , Mjøen Svendsen John S. , Fugelli Anders , Hodge James J. L. 

TITLE=DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer’s Disease-Down Syndrome Phenotypes

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.881385

DOI=10.3389/fphar.2022.881385

ISSN=1663-9812

ABSTRACT=<p>Alzheimer’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 <italic>Amyloid Precursor Protein</italic> (<italic>APP</italic>) into Amyloid-β and <italic>Microtubule Associated Protein Tau</italic> (<italic>MAPT</italic>) 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 <italic>APP</italic> and other AD-associated genes, such as <italic>DYRK1A</italic> (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 <italic>Drosophila</italic> models with targeted overexpression of human <italic>Tau</italic>, human <italic>Amyloid-β</italic> or the fly orthologue of <italic>DYRK1A</italic>, called <italic>minibrain</italic> (<italic>mnb</italic>). 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.</p>