1 Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 6041-Gosselies, Belgium.
Brain. 2014 Feb;137(Pt 2):537-52. doi: 10.1093/brain/awt344. Epub 2014 Jan 8.
ITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer's disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer's disease might be related to an increased activity of ITPKB. We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. No impact on pathology was observed in the 5X familial Alzheimer's disease mouse model when a catalytically inactive ITPKB protein was overexpressed. Together, our results point to the ITPKB/inositol 1,3,4,5-tetrakisphosphate/extracellular signal-regulated kinases 1/2 signalling pathway as an important regulator of neuronal cell apoptosis, APP processing and tau phosphorylation in Alzheimer's disease, and suggest that ITPKB could represent a new target for reducing pathology in human patients with Alzheimer's disease with ITPKB expression.
ITPKB 将肌醇 1,4,5-三磷酸磷酸化为肌醇 1,3,4,5-四磷酸，并控制各种造血细胞中的信号转导。令人惊讶的是，据报道，与对照相比，阿尔茨海默病患者大脑皮层中的 ITPKB 信使 RNA 水平显著增加。由于细胞外信号调节激酶 1/2 的激活在阿尔茨海默病大脑中增加，并且 ITPKB 是一些造血细胞中细胞外信号调节激酶 1/2 激活的调节剂，我们测试了这种在阿尔茨海默病中增加的激活是否可能与 ITPKB 的活性增加有关。我们在这里显示，与对照相比，大多数阿尔茨海默病患者的大脑皮层中 ITPKB 蛋白水平增加了 3 倍，并在与淀粉样斑块相关的变性神经突中积累。在小鼠神经母细胞瘤 Neuro-2a 细胞中，Itpkb 的过表达与细胞凋亡增加和β-分泌酶 1 活性增加有关，导致淀粉样-β肽的过度产生。在这个细胞模型中，丝裂原活化蛋白激酶激酶 1/2 的抑制剂完全阻止了淀粉样-β肽的过度产生。在小鼠前脑神经元中过表达 ITPKB 不足以诱导淀粉样斑块形成或 tau 过度磷酸化。然而，在 5X 家族性阿尔茨海默病小鼠模型中，神经元 ITPKB 的过表达显著增加了细胞外信号调节激酶 1/2 的激活和β-分泌酶 1 的活性，导致阿尔茨海默病病理加重，如星形胶质细胞增生、淀粉样-β40 肽产生和 tau 过度磷酸化增加。在过表达无催化活性 ITPKB 蛋白的 5X 家族性阿尔茨海默病小鼠模型中，对病理没有影响。总之，我们的结果表明，ITPKB/肌醇 1,3,4,5-四磷酸/细胞外信号调节激酶 1/2 信号通路是阿尔茨海默病中神经元细胞凋亡、APP 加工和 tau 磷酸化的重要调节剂，并表明 ITPKB 可能代表一种新的靶点，用于减少具有 ITPKB 表达的人类阿尔茨海默病患者的病理。
