Reconstruction of neuronal network in neurodegenerative disorders

在神经元网络的形成过程中，单个神经元的形态起着重要的作用。早老素1 （PS1）突变与家族性阿尔茨海默病（AD）高度相关。我们用SH-SY5Y细胞检测了PS1对神经元形态的影响。过表达显性阴性的PS1诱导神经突形成受损，而野生型和ad相关突变体的PS1与天然细胞相比没有改变细胞形态。肌动蛋白细胞骨架相关蛋白，如Wiskott-Aldrich综合征蛋白（N-WASP），仅在表达显性阴性PS1的细胞中减少。因此，PS1可能参与了SH-SY5Y细胞的神经生成和形态改变。此外，我们检测了肌动蛋白细胞骨架相关蛋白N-WASP、WASP家族verprolin-homologous protein （WAVE）在出生后发育大鼠脑中的表达水平和分布。这些因素在发育过程中逐渐增加，并且似乎存在于突触丰富的区域。因此，N-WASP和WAVE可能通过调节肌动蛋白细胞骨架参与正常脑发育和突触可塑性。大脑中动脉闭塞和再灌注导致大鼠行为障碍，神经网络大面积损伤。我们研究了大鼠培养的小胶质细胞、小鼠胚胎干细胞（ES）细胞和ES细胞衍生的神经元样细胞（ES- n）移植对缺血大鼠行为功能的影响。通过移植，局灶性脑缺血引起的行为功能障碍明显受到抑制。行为功能障碍的有效改善可能与外源性小胶质细胞的神经保护作用以及ES和ES- n细胞移植后多巴胺能神经元功能的恢复有关。为了研究帕金森病（PD）的移植策略，我们评估了纹状体（ST）和黑质（SN），或ST和丘脑底核（STN）的双重移植是否能诱导6-羟多巴胺损伤大鼠的功能恢复。将小鼠ES-N移植到ST中，明显减少了药物诱导的旋转，但仅移植到STN或SN中则没有。双移植在恢复旋转行为方面也很有效。这些结果表明，ST的参与和作为移植的地方和ES-N的数量是影响偏瘫行为的关键因素。DJ-1最近被证明与家族性帕金森病PARK7的发病有关。在6-羟多巴胺损伤大鼠中，我们进一步发现同时和/或后注射重组野生型而非突变型人DJ-1具有神经保护作用。少

In the formation of neuronal network, morphology of individual neuron plays an important role. Mutations in presenilin 1 (PS1) are highly related to familial Alzheimer's disease (AD). We examined the effects of PS1 on neuronal morphology using SH-SY5Y cells. Overexpression of dominant-negative PS1 induced impairment of neurite formation, while those of wild-type and AD-related mutant PS1 did not change cellular morphology compared with native cells. Actin cytoskeleton-related proteins, such as Wiskott-Aldrich syndrome protein (N-WASP), were decreased only in cells expressing dominant-negative PS1. Therefore, PS1 may be involved in neuritogenesis and morphological change in SH-SY5Y cells. Furthermore, we examined the expression levels and distributions of actin cytoskeleton-related proteins, such as N-WASP, WASP family verprolin-homologous protein (WAVE) in the rat brain during postnatal development. These factors were progressively increased during development, and seemed to exist in t … More he synapse-rich areas. Thus, N-WASP and WAVE may participate in normal brain development and synaptic plasticity by regulating the actin cytoskeleton. Occlusion of the middle cerebral artery (MCA) and reperfusion caused behavioral dysfunction with massive damage of neuronal network. We examined the effects of transplantation of rat cultured microglia, mouse embryonic stem (ES) cells or ES cell-derived neuron-like (ES-N) cells on behavioral function in ischemic rats. By the transplantation, focal ischemia-induced behavioral dysfunction was significantly inhibited. The effective improvement of behavioral dysfunction may be due to the neuroprotective effect of exogenous microglia and the recovery of dopaminergic neuronal function by the transplantation of ES and ES-N cells. To investigate a transplantation strategy for Parkinson's disease (PD), we assessed whether double-transplants in the striatum (ST) and substantia nigra (SN), or ST and subthalamic nucleus (STN) induce functional recovery in 6-hydroxydopamine-lesioned rats. Drug-induced rotation was significantly reduced by transplantation of mouse ES-N into the ST, but not the STN or SN alone. Double-transplantation was also effective at recovering rotational behavior. These results suggest that both the involvement of ST and as a place of transplantation and the number of ES-N are essential factors for efficacy on hemiparkinsonian behaviors. DJ-1 has recently been shown to be responsible for onset of familial PD, PARK7. Using 6-hydroxydopamine-lesioned rats, we further found that the simultaneous and/or post injection of recombinant wild type, but not mutant human DJ-1 had neuroprotective effect. Less