TY - JOUR
T1 - Altered regulation of tau phosphorylation in a mouse model of down syndrome aging
AU - Sheppard, Olivia
AU - Plattner, Florian
AU - Rubin, Anna
AU - Slender, Amy
AU - Linehan, Jacqueline M.
AU - Brandner, Sebastian
AU - Tybulewicz, Victor L.J.
AU - Fisher, Elizabeth M.C.
AU - Wiseman, Frances K.
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Down syndrome
KW - DYRK1A
KW - GSK-3β
KW - Phosphorylation
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=84856955428&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2011.06.025
DO - 10.1016/j.neurobiolaging.2011.06.025
M3 - Article
AN - SCOPUS:84856955428
VL - 33
SP - 828.e31-828.e44
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 4
ER -