University College London Institute of Neurology, London, UK.
Neurobiol Aging. 2012 Apr;33(4):828.e31-44. doi: 10.1016/j.neurobiolaging.2011.06.025. Epub 2011 Aug 16.
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.
唐氏综合征（DS）是由于人类 21 号染色体（Hsa21）三体引起的，与阿尔茨海默病（AD）的风险增加有关。在这里，我们使用独特的唐氏综合征跨染色体 Tc1 小鼠模型研究了 Hsa21 三体对蛋白 tau 的影响，tau 在阿尔茨海默病中过度磷酸化。我们表明，在年老的，但不是年轻的，Tc1 小鼠中，tau 的磷酸化在一个被认为是由 Hsa21 编码的激酶双特异性酪氨酸-(Y)-磷酸化调节激酶 1A（DYRK1A）靶向的位点增加。我们表明 DYRK1A 在年轻和年老的 Tc1 小鼠中上调，但年轻的三体小鼠可能免受异常磷酸化 tau 的积累。我们观察到关键的 tau 激酶糖原合酶激酶 3-β（GSK-3β）在年老的 Tc1 大脑中在一个抑制性位点被异常磷酸化，这可能降低总糖原合酶激酶 3-β活性。在患有 DS 的人中，也可能发生类似的机制。
