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

R. Velazquez, B. Meechoovet, A. Ow, C. Foley, A. Shaw, B. Smith, S. Oddo, C. Hulme, Travis Dunckley

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StatePublished - Jan 1 2019

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Alzheimer Disease
Neurofibrillary Tangles
Pathology
Amyloid Plaques
Amyloid beta-Protein Precursor
Amyloid beta-Peptides
Brain Diseases
Amyloid
Therapeutics
Phosphorylation
Inhibition (Psychology)
Dyrk kinase
Proteins

Keywords

  • 3xTg-AD
  • Alzheimer’s disease
  • Amyloid
  • DYRK1A
  • Tau
  • Therapeutics

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice. / Velazquez, R.; Meechoovet, B.; Ow, A.; Foley, C.; Shaw, A.; Smith, B.; Oddo, S.; Hulme, C.; Dunckley, Travis.

In: Molecular Neurobiology, 01.01.2019.

Research output: Contribution to journalArticle

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