Abstract：
Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer\'s disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected. Current evidence suggests that APP could also regulate neurite growth through its role in the actin cytoskeleton, in part by influencing p21-activated kinase (PAK) activity. The latter effect is carried out by an increased abundance of the caspase cleavage-released carboxy-terminal C31 fragment. In this work, using a neuronal cell line named CTb, which derived from the cerebral cortex of a trisomy 16 mouse, an animal model of human DS, we observed an overexpression of APP, elevated caspase activity, augmented cleavage of the C-terminal fragment of APP, and increased PAK1 phosphorylation. Morphometric analyses showed that inhibition of PAK1 activity with FRAX486 increased the average length of the neurites, the number of crossings per Sholl ring, the formation of new processes, and stimulated the loss of processes. Considering our results, we propose that PAK hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS, and therefore we suggest that PAK1 may be a potential pharmacological target.
摘要：
唐氏综合症（DS）的特征是21号染色体的三体性和与人类神经元形态改变有关的认知缺陷，以及动物模型。淀粉样前体蛋白（APP）的编码基因存在于常染色体21中，其在DS中的过表达与神经元功能障碍有关，认知缺陷，和老年痴呆症一样的疾病。特别是,神经元扩展过程和分支的能力受到影响。目前的证据表明，APP还可以通过其在肌动蛋白细胞骨架中的作用来调节神经突生长，部分通过影响p21激活的激酶（PAK）活性。后一种作用是通过增加caspase裂解释放的羧基末端C31片段的丰度来实现的。在这项工作中,使用名为CTb的神经元细胞系，它来自16三体小鼠的大脑皮层，人类DS的动物模型，我们观察到APP的过度表达，caspase活性升高，APP的C端片段的增强切割，和增加PAK1磷酸化。形态学分析显示，用FRAX486抑制PAK1活性增加了神经突的平均长度，每个Sholl环的交叉数量，形成新的过程，并刺激了过程的损失。考虑到我们的结果，我们认为PAK过度磷酸化会损害DS细胞模型中的神经突生长和重塑，因此，我们认为PAK1可能是一个潜在的药理靶点。
