Date Published: August 04, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Caterina Branca, Darren M. Shaw, Ramona Belfiore, Vijay Gokhale, Arthur Y. Shaw, Christopher Foley, Breland Smith, Christopher Hulme, Travis Dunckley, Bessie Meechoovet, Antonella Caccamo, Salvatore Oddo.
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‐β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects about 5.5 million people in the United States and 40 million worldwide (Alzheimer’s, 2015). There is an urgent need for developing new therapeutic approaches as the current FDA approved medications have no effects on the progression of the disease. If the current status quo is not altered by the introduction of new therapeutic strategies able to slow down or halt the progression of the disease, it is estimated that by 2050, 12 million people in the United States will have AD (Alzheimer’s, 2015).
There are no current means to slow the progression of AD effectively. In this proof‐of‐concept study, we report that Dyrk1 is a valid new target for AD treatment and show that its chronic inhibition reduced Aβ and tau pathology and ameliorated cognitive deficits in 3xTg‐AD mice. These data are consistent with previous results indicating that CX‐4945, a selective and potent Dyrk1a inhibitor, reduces tau pathology in multiple systems (Kim et al., 2016). Taken together these results clearly indicate that Dyrk1 represents a valid therapeutic target for AD and support the development of new, effective, and clinically safe compounds aimed at reducing Dyrk1 activity.
This work was supported by grants to S.O. from the Arizona Alzheimer’s Consortium and the National Institutes of Health (R01 AG037637).
Christopher Hulme and Travis Dunckley have filed a provisional patent for the use of Dyrk‐inh as a treatment for Alzheimer’s disease. The other authors have nothing to disclose.
CB designed the experiments, carried out the dosing of the mice, the biochemical and histological experiments, analyzed the data, and wrote the manuscript. DMS performed the behavioral experiments and contributed to the writing of the manuscript. RB performed some of the biochemical experiments and contributed to the writing of the manuscript. VG, AYS, CF, BS, CH, and TD developed the compound and contributed to the writing of the manuscript. AC analyzed the data and contributed to the writing of the manuscript. SO designed the study, analyzed the data, and wrote the manuscript.