Dyrk1A-mediated phosphorylation of Presenilin 1: a functional link between Down syndrome and Alzheimer's disease

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the gamma-secretase complex in the generation of beta-amyloid (A beta), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased A beta production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which A beta is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr(354) and that this phosphorylation increases gamma-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphos-phorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the A beta pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.