Altered regulation of tau phosphorylation in a mouse model of down syndrome aging

Olivia Sheppard, Florian Plattner, Anna Rubin, Amy Slender, Jacqueline M. Linehan, Sebastian Brandner, Victor L J Tybulewicz, Elizabeth M C Fisher, Frances K. Wiseman

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
JournalNeurobiology of Aging
Volume33
Issue number4
DOIs
Publication statusPublished - Apr 2012

    Fingerprint

Keywords

  • Alzheimer disease
  • Down syndrome
  • DYRK1A
  • GSK-3β
  • Phosphorylation
  • Tau

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Sheppard, O., Plattner, F., Rubin, A., Slender, A., Linehan, J. M., Brandner, S., ... Wiseman, F. K. (2012). Altered regulation of tau phosphorylation in a mouse model of down syndrome aging. Neurobiology of Aging, 33(4). https://doi.org/10.1016/j.neurobiolaging.2011.06.025