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Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice

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Abstract

There is a critical need for new treatment approaches that can slow or prevent the progression of Alzheimer’s disease (AD). Targets that act simultaneously on multiple relevant pathways could have significant therapeutic potential. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) phosphorylates both amyloid precursor protein (APP) and tau. Dyrk1a is upregulated in post-mortem brains of AD patients, and such elevated expression is associated with cognitive deficits. We previously demonstrated that small molecule inhibition of Dyrk1 is well-tolerated and reduces amyloid plaques and pathological forms of tau in 3xTg-AD mice if administered after formation of these pathologies. However, while insoluble forms of hyperphosphorylated tau were reduced by Dyrk1 inhibition, overt neurofibrillary tangle (NFT) pathology remained unchanged. Herein, we specifically test the hypothesis that inhibition of Dyrk1 prior to NFT formation will delay the onset of pathology. 3xTg-AD mice were treated chronically, beginning at 6 months of age, prior to NFT pathology. Mice were dosed daily for either 3 or 6 months and amyloid and tau pathology were assessed. We show that chronic Dyrk1 inhibition reduces insoluble forms of amyloid beta peptides (Aβ) and hyper-phosphorylated tau long-term and that these reductions are associated with dramatic delay in the onset of both amyloid plaques and NFTs. In addition, we show that DYR219, a potent and selective small molecule Dyrk1 inhibitor, induces degradation of Dyrk1a protein, likely contributing to the efficacy of this small molecule approach in vivo. Collectively, these results suggest that therapeutic strategies targeting tau phosphorylation will show the greatest effect if administered very early in the pathogenesis of AD.

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Funding

This work was supported by grants R01 AG037637 to S.O., from the Alzheimer’s Drug Discovery Foundation to C.H., and from the Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute to T.D.

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Author notes

  1. C. Hulme and Travis Dunckley contributed equally to this work.

Authors and Affiliations

  1. Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, 85281, USA

    R. Velazquez, A. Ow, S. Oddo & Travis Dunckley

  2. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA

    B. Meechoovet

  3. Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA

    C. Foley, A. Shaw, B. Smith & C. Hulme

  4. School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA

    S. Oddo

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  1. R. Velazquez
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Correspondence to Travis Dunckley.

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Animal care and treatments were in accordance with the applicable regulation of the vivarium (The Institutional Animal Care and Use Committee of the Arizona State University).

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Supplemental Table 1

PK results for DYR219. Shown are all time points and replicates detecting brain levels of DYR219 following a single IP injection at 12.5 mg/kg. Summary values are also listed beneath the table. (XLSX 13 kb)

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Velazquez, R., Meechoovet, B., Ow, A. et al. Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice. Mol Neurobiol 56, 8364–8375 (2019). https://doi.org/10.1007/s12035-019-01684-9

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