Dyrk1 inhibition improves Alzheimer's disease‐like pathology

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.

Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

“…Finally, while the apparent complementary actions of DYRK1A inhibitors and TGFb superfamily inhibitors, illustrated in Figure 7A, likely explain much of the apparent synergy, they are unlikely the exclusive mechanism for the observed synergy, as evidenced by the ability of harmine alone to modulate expression and abundance of TGFb superfamily members ( Figure 3A; Table S2). Indeed, several reports indicate that DYRK1A can phosphorylate a broad range of targets in addition to the NFaT family, including Tau, TP53, p27 CIP , and the DREAM complex member LIN52 (Abdolazimi et al, 2018;Branca et al, 2017;Litovchick et al, 2011;Park et al, 2010;Sadasivam and DeCaprio, 2013). We thus speculate that currently unknown additional targets likely exist that may lead to destabilization and/or dephosphorylation of SMADs as observed in Figure 3A.…”

Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase

“…In the first decade of life, a time when there is little amyloid deposition [34,35], plasma Aβ42 levels were on average a little higher (~1.6 fold) in DS than the expected 1.5-fold elevation due to gene dosage. Why this should be is unclear, but it is worth noting that several AD risk factors are encoded on chromosome 21 [2] and these might contribute to either enhanced amyloidogenic processing of APP [36,37] or reduced degradation of Aβ [38]. Also, neuronal Aβ production is activity dependent [39] and in DS there is evidence of aberrant hyperactivity during development and early life [40] that could contribute to higher Aβ levels.…”

Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease

“…Inhibition of DYRK1A may reduce these factors and the pathogenesis of AD. Proof‐of‐concept studies with DYRK1A inhibitors have demonstrated a reduction in amyloid pathology, insoluble tau phosphorylation, and neuroprotection in mice (Branca et al, ; Naert et al, ; Neumann et al, ). Previous attempts at modulating kinases in patients (GSK‐3β) may have failed due to the low potency and limited bioavailability of those compounds.…”