title: Altered regulation of tau phosphorylation in a mouse model of down syndrome aging.
abstract: Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.
authors.affiliation: University College London Institute of Neurology, London, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Sheppard
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.forename: Anna
authors.initials: A
authors.lastname: Rubin
authors.forename: Amy
authors.initials: A
authors.lastname: Slender
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Frances K
authors.initials: FK
authors.lastname: Wiseman
mesh_terms: D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse