Abstract
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.
Highlights
Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21
One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau
These results provide the first in vivo evidence for a physiological role of dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD
Summary
DS patients suffer various symptoms, including congenital heart defects, immune and endocrine system defects, mental retardation, and early onset of Alzheimer disease (AD) [3] Both DS and AD patients have pathological hallmarks, amyloid plaques and neurofibrillary tangles (NFTs) that are insoluble deposits made of proteins called -amyloid (A) and hyperphosphorylated Tau, respectively (4 – 6). Tau protein was phosphorylated at Ser-202 and Ser-404 residues by Dyrk1A in vitro, and the levels of the phosphorylation at those residues were increased in DYRK1A TG mice These results indicate that the overexpression of DYRK1A in DS brains may contribute to early onset of AD pathology through the hyperphosphorylation of Tau
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