Abstract
SummaryThere 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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects about 5.5 million people in the United StatesAccepted for publication 19 June 2017 and 40 million worldwide (Alzheimer’s, 2015)
We found that at this concentration, Dyrk1-inh inhibited >99% of dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) and Dyrk1b activity (IC50: 124 and 129 nM, respectively; Fig. S2B)
We focused on amyloid precursor protein (APP)/ Thr668 as Dyrk1a is one of the known protein kinases responsible for phosphorylation of APP at this specific epitope (Ryoo et al, 2008)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects about 5.5 million people in the United StatesAccepted for publication 19 June 2017 and 40 million worldwide (Alzheimer’s, 2015). 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). Pathological tau is hyperphosphorylated and produces soluble and insoluble inclusions, which form neurofibrillary tangles (NFTs) characteristic of AD and other tauopathies (Medina et al, 2016) To this end, inhibiting the activity of known tau kinases could be a valid approach to reduce the formation of NFTs (Rojas & Boxer, 2016). Full-length APP undergoes several post-translational modifications, including phosphorylation at specific epitopes that regulates its half-life and affinity for BACE1 (Lee et al, 2003; Ma et al, 2012). This is intriguing as reducing APP levels and/or reducing its affinity of BACE1 could be valid approaches to lower Ab levels
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