Most individuals with Down syndrome show early onset of Alzheimer disease (AD), 
resulting from the extra copy of chromosome 21. Located on this chromosome is a 
gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 
1A (DYRK1A). One of the pathological hallmarks in AD is the presence of 
neurofibrillary tangles (NFTs), which are insoluble deposits that consist of 
abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the 
Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the 
physiological significance of this phosphorylation, an analysis was made of the 
amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that 
overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently 
generated. A significant increase in the amount of pT212 was found in the brains 
of DYRK1A transgenic mice when compared with age-matched littermate controls. We 
further examined whether Dyrk1A phosphorylates other Tau residues that are 
implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and 
Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of 
Tau to promote microtubule assembly. Following this, using mammalian cells and 
DYRK1A TG mouse brains, it was demonstrated that the amounts of 
phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are 
high. These results provide the first in vivo evidence for a physiological role 
of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of 
the DYRK1A gene contributes to the early onset of AD.