β-Carboline Compounds, Including Harmine, Inhibit DYRK1A and Tau Phosphorylation at Multiple Alzheimer’s Disease-Related Sites

Introduction

DYRK1A is a dual-specificity kinase encoded on chromosome 21 within the Down syndrome critical region and has been implicated in neurodevelopmental abnormalities and cognitive deficits when overexpressed. Previous cellular and transgenic studies have linked DYRK1A activity to both amyloid and tau pathologies observed in Down syndrome and sporadic Alzheimer's disease (AD), and DYRK1A protein has been detected in neurofibrillary tangles. Earlier work by the authors and others indicated that DYRK1A phosphorylates tau at several sites associated with AD-related tau dysfunction, raising the kinase as a potential therapeutic target to modify tau pathology. Frost and colleagues set out to test whether harmine, a b-carboline alkaloid reported to inhibit DYRK1A, and a panel of related b-carboline derivatives could inhibit DYRK1A-dependent phosphorylation of tau at multiple AD-relevant sites. The study combines RNAi, cell-based assays in a tau-overexpressing neuroglioma line, and in vitro kinase assays with recombinant proteins to (1) map DYRK1A-dependent tau phosphorylation sites, (2) measure the effect of harmine and related compounds on phosphorylated and total tau, and (3) relate compound structure to inhibitory potency against DYRK1A-mediated phosphorylation.