Dual‐specificity tyrosine(Y)‐phosphorylation regulated kinase 1A‐mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease

Abstract

Most individuals with Down Syndrome (DS) show an early‐onset of Alzheimer’s disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode β‐amyloid (Aβ) precursor protein (APP ), a key protein involved in the pathogenesis of AD, and dual‐specificity tyrosine(Y)‐phosphorylation regulated kinase 1A (DYRK1A ), a proline‐directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A‐mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho‐APP and Aβ are increased in the brains of transgenic mice that over‐express the human DYRK1A protein. Furthermore, we show that the amounts of phospho‐APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over‐expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.