There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-beta (Ab) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Ab levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/626504 |
| Date | 10 1900 |
| Creators | Branca, Caterina, Shaw, Darren M., Belfiore, Ramona, Gokhale, Vijay, Shaw, Arthur Y., Foley, Christopher, Smith, Breland, Hulme, Christopher, Dunckley, Travis, Meechoovet, Bessie, Caccamo, Antonella, Oddo, Salvatore |
| Contributors | Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Univ Arizona, Dept Chem & Biochem, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA, Division of Drug Discovery and Development; Department of Pharmacology and Toxicology; College of Pharmacy; The University of Arizona; Tucson AZ 85721 USA, Division of Drug Discovery and Development; Department of Pharmacology and Toxicology; College of Pharmacy; The University of Arizona; Tucson AZ 85721 USA, Department of Chemistry & Biochemistry; The University of Arizona; Tucson AZ 85721 USA, Division of Drug Discovery and Development; Department of Pharmacology and Toxicology; College of Pharmacy; The University of Arizona; Tucson AZ 85721 USA, Division of Drug Discovery and Development; Department of Pharmacology and Toxicology; College of Pharmacy; The University of Arizona; Tucson AZ 85721 USA, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA, Neurogenomics Division; Translational Genomics Research Institute; Phoenix AZ 85004 USA, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA, The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute; Arizona State University; Tempe AZ 85287 USA |
| Publisher | WILEY |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License. |
| Relation | http://doi.wiley.com/10.1111/acel.12648 |
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