Correlation of Alzheimer’s disease with Wnt signaling pathway and neural stem cells

doi:10.3969/j.issn.2095-4344.2013.19.023

Abstract

Abstract:

BACKGROUND: The pathological mechanism of Alzheimer’s disease involves inherited, environmental and immunological factors. Strong evidence exists that Wnt signaling pathway is closely related to the pathological process of Alzheimer’s disease. There is also evidence that Wnt signaling pathway plays a crucial effect on the proliferation of neural stem cells.
OBJECTIVE: To review the relationship between pathological process of Alzheimer’s disease and Wnt signaling pathway and effects of Wnt signaling on proliferation and differentiation of neural stem cells, providing theoretical evidence for treatment of Alzheimer’s disease.
METHODS: A computer-based online search of PubMed databases was undertaken for papers addressing the relationship of Alzheimer’s disease and Wnt signaling pathway and the correlation between Wnt signaling pathway and neural stem cells using the key words “Alzheimer’s disease, Wnt signaling pathway, NSCs, stem cell differentiation, amyloid-β protein, protein Tau”. After excluding papers with repetitive contents, 50 papers were suitable for final analysis.
RESULTS AND CONCLUSION: Treatment of neurodegenerative diseases characterized by neuron loss using neural stem cell transplantation has become a gradually increased research area. However, how to regulate neural stem cells to differentiate into specific neurons has been proposed. Signal transduction plays an important role in the differentiation of neural stem cells and Wnt signaling pathway is an important extracellular factor of regulating the proliferation and differentiation of neural stem cells. Inactivation of Wnt signaling pathway promotes the progression of Alzheimer’s disease, and activation of Wnt signaling pathway protects hippocampal neurons and promotes the differentiation of neural stem cells. This may provide novel therapeutic methods for Alzheimer’s disease.

CLC Number:

R318

Wang Wei, Zhang Hai-ting, Wang Shu-hui, Zhang Yong-bo. Correlation of Alzheimer’s disease with Wnt signaling pathway and neural stem cells[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(19): 3566-3572.

Figures/Tables 1

2.1 Wnt信号通路 Wnt基因是一种原癌基因，其命名来源于1973年Sharma等发现的果蝇无翼基因(wingless)与1982年Nusse等对小鼠乳腺肿瘤研究中发现的int-1基因为同源基因，因此将两者合并命名为Wnt基因[1-2]。Wnt蛋白是由Wnt基因编码的一系列分泌型糖蛋白，长度在350-400个氨基酸之间，其羧基末端含有22-24个高度保守的半胱氨酸残基[3]。Wnt蛋白是Wnt信号通路的的起始蛋白，通过自分泌或旁分泌与细胞膜上的相应受体结合，进而激活细胞内的各级信号分子来调控靶基因的表达[4]。Wnt信号通路在从原肠胚和早期结构形成到器官发生的整个胚胎发育过程中是非常关键的[5]，在成年有机体内对于保持组织的同源性和干细胞的调节方面也起着主要的作用[6]。总之Wnt信号通路控制着体内多种程序，例如细胞的增殖、自我更新、细胞分化、细胞极性、细胞死亡等过程[7]。Wnt信号通路在多种生物进程中复杂而关键的作用表明它的失调会引起多种疾病，例如癌症、先天性疾病和退行性疾病[8-9]。根据细胞内β连环蛋白是否参与信号通路，将Wnt信号传导通路分为经典Wnt信号传导通路和非经典Wnt信号传导通路。 2.1.1 经典Wnt信号通路(Wnt/β-连环蛋白信号通路) 目前研究较为深入及广泛的Wnt通路是依赖β-连环蛋白的Wnt信号通路，因此该通路被称为是经典信号通路。β-连环蛋白是经典Wnt信号通路的关键组成成分，也是其重要的调控位点。大量研究已经证实经典Wnt信号通路与疾病的发生、干细胞的分化、组织器官的修复等相关，在脊椎动物体内Wnt/β-连环蛋白信号通路的失活会引起心脏病[10]、肿瘤和阿尔茨海默病[11-12]。该通路的主要机制为Wnt蛋白存在时，与细胞膜上的7次跨膜的G蛋白偶联受体卷曲蛋白及共同受体低密度脂蛋白受体相关蛋白5/6结合，激活细胞基质蛋白散乱蛋白，从而抑制糖原合成激酶的活性，使未磷酸化的β-连环蛋白在细胞质中积聚并转移到细胞核中，与淋巴增强因子/T细胞因子家族转录因子结合，启动靶基因的转录，进而产生多种细胞效应[13]。在缺乏Wnt蛋白的情况下，由胞质中的糖原合成酶激酶3β、腺瘤息肉蛋白、轴素共同构成的降解复合体迅速将细胞质中的β-连环蛋白磷酸化，然后磷酸化的β-连环蛋白被泛素化，最终被蛋白酶体降解[14]。虽然在细胞中β-连环蛋白不断地在合成，但是其在胞质中仍维持在较低水平，从而影响β-连环蛋白的核转移及基因表达。 2.1.2 非经典Wnt信号通路非经典Wnt信号通路无β-连环蛋白的参与，而是其他一些离子或蛋白的参与。目前研究较多的主要包括以下两种，Wnt/Ca2+通路主要通过Wnt、Fz介导增加细胞内的钙离子浓度，激活蛋白激酶C和其他钙离子依赖性蛋白激酶来发挥作用[15]。Wnt/PCP(planar cell polarity)通路主要是通过FZ、Dsh介导的依次激活小G蛋白(Rho和 Rac)，Jun N-未端激酶(JNK)和Rho激酶来调控细胞骨架形成、组织极性及细胞迁移[16]。 2.2 阿尔茨海默病与Wnt信号通路阿尔茨海默病的病理学标志是β淀粉样蛋白聚集成的老年斑和过度磷酸化的微管相关蛋白tau蛋白组成的神经纤维缠结[17]。β淀粉样蛋白的聚集和tau蛋白的过度磷酸化产生神经毒性，最终导致海马神经元的大量缺失。而Wnt信号通路参与了有功能的完整的神经元产生的大部分过程，大量研究表明Wnt信号通路在阿尔茨海默病的发生中起着重要的作用。 2.2.1 Wnt信号通路与β淀粉样蛋白的关系 β淀粉样蛋白是由存在于细胞膜上的淀粉样前体蛋白经过β蛋白酶和γ蛋白酶的两步酶切所形成，单体β淀粉样蛋白会逐渐聚合成寡聚状态，最终产生神经毒性。淀粉样前体蛋白、早老素1等基因的突变会导致β淀粉样蛋白的产生和清除动态失衡，造成β淀粉样蛋白特别是β淀粉样蛋白42过度积累，这可能是阿尔茨海默病发生的原因之一[17]。β淀粉样蛋白在体内主要有两种形式：β淀粉样蛋白40和β淀粉样蛋白42，其中β淀粉样蛋白42被认为更容易形成寡聚体而产生神经毒性。β淀粉样蛋白寡聚状态的形成被认为是阿尔茨海默病发病过程中最重要的环节[18]。 β淀粉样蛋白会与FZ的半胱氨酸富集区域相结合，该区域与Wnt蛋白和FZ的结合区域相同或非常接近，阻止了经典Wnt信号通路，从而影响了β连环蛋白的积聚、核转移和Wnt靶基因的表达[19]。β淀粉样蛋白对Wnt信号通路的阻断除直接引起海马神经元的破坏外，还会引起神经干细胞的分化减低，而Wnt3a蛋白可以增加β淀粉样蛋白42处理后的海马前体细胞的分化[20]。淀粉样前体蛋白经酶切后除产生β淀粉样蛋白外，还会产生胞内结构域是经典Wnt信号通路的抑制剂，在神经元的增殖及分化中起调节作用[21-22]。激活Wnt信号通路会阻止β淀粉样蛋白引起的神经毒性。阿尔茨海默病患者细胞质中β连环蛋白的水平显著降低[23]。用锂抑制糖原合成酶激酶3β的活性后，β连环蛋白的水平会增高激活Wnt信号通路来保护大鼠的海马神经元免受β淀粉样蛋白引起的损害[24]。大量体外研究表明用Wnt3a条件培养基激活经典Wnt信号通路同样能够抑制β淀粉样蛋白引起的神经毒性作用[25-26]。这些证据表明Wnt信号功能的持续缺失与阿尔茨海默病患者中观察到的β淀粉样蛋白引起的神经退行性变相关。β淀粉样蛋白可以通过抑制Wnt信号通路的功能来影响靶基因的表达，从而产生神经毒性最终导致大量神经元的缺失。研究某种药物来激活Wnt信号通路从而抑制β淀粉样蛋白的神经毒性成为治疗阿尔茨海默病又一新思路。 2.2.2 Wnt信号通路与tau蛋白的关系 Tau蛋白是一种含磷的微管相关蛋白，位于神经元的突触上。Tau蛋白可以在微管之间形成横桥，维持并加强微管的稳定性，诱导微管成束。在正常成年人脑内的Tau蛋白呈适度磷酸化状态，磷酸化和去磷酸化的平衡调控着神经元细胞骨架的稳定和轴突的形态[27]。阿尔茨海默病患者神经元内tau蛋白的磷酸化和去磷酸化的平衡被打破，呈过度磷酸化状态，过度磷酸化的tau蛋白相互聚集形成神经纤维缠结，丧失与微管蛋白结合的能力，从而影响微管的集聚和细胞骨架的稳定性,最终引起神经元的死亡。糖原合成酶激酶3β是哺乳动物胞质内的一个丝氨酸/苏氨酸激酶，是Wnt信号通路的一个重要的负调控因子，它通过对另外两个蛋白β连环蛋白、APC磷酸化而起作用。大量的证据表明糖原合成酶激酶3β与tau蛋白的过度磷酸化及阿尔茨海默病患者的记忆损害相关。在阿尔茨海默病患者脑内的海马区域及突触后膜上糖原合成酶激酶3β是高度表达的[28]。在糖原合成酶激酶3β转基因小鼠脑内发现了tau蛋白的过度磷酸化和神经元的退行性变，而用糖原合成酶激酶3β抑制剂锂处理后可以预防tau的过度磷酸化和纤维缠结的形成[29]。同样有研究显示，用锂长期处理阿尔茨海默病患者及神经系统退行性变的小鼠模型可以改善其认知功能障碍[30]。Enqel等[31]发现，糖原合成酶激酶3β能使微管相关蛋白Tau的大多数丝氨酸-苏氨酸位点磷酸化，形成大量的双螺旋结构，引起神经元的死亡。并且在糖原合成酶激酶3β过度表达的老鼠的前脑中，能够重现阿尔茨海默病的神经病理过程，比如：Tau蛋白过磷酸化，星形细胞的反应性增生和间歇性的学习认知功能障碍等。这些证据表明Wnt信号通路的负调控因子糖原合成酶激酶3β可以通过对tau蛋白的过度磷酸化破坏神经元产生认知功能障碍，糖原合成酶激酶3β的抑制剂的研究成为治疗阿尔茨海默病的再一突破口。 2.3 Wnt信号通路与神经干细胞的关系神经干细胞是一类来源于神经系统的多能干细胞，具有自我更新及通过不对称分裂产生多种神经细胞的能力。在成年人的中枢神经系统中，持续的神经形成只发生在两个特定的区域：侧脑室的室管膜下区和海马齿状回亚颗粒区域[32]。多种内在和外在因素可以调节神经形成，例如性别、年龄、激素、神经递质、生长因子、行为、药物和病理性刺激等在干细胞的分化、迁移和存活等方面发挥作用[33]。随着海马神经元不断地凋亡，新生海马神经元的补充对于一些学习及记忆程序是非常关键的[34]。阿尔茨海默病患者新生神经元的产生及成熟能力下降，不能够补偿丢失的海马神经元，导致海马神经元进行性下降，最终造成认知功能的严重受损。只有将外源性的能够分化为成熟的海马神经元的干细胞移植到阿尔茨海默病患者海马区域并分化为有功能的神经元，从而代偿丢失的海马神经元的功能，才能够从根本上纠正海马神经元的缺失及其引起的一系列症状[35]。大量研究显示神经干细胞或神经元前体细胞移植入患者脑内后可以迁移到脑部受损区域，分化为有功能的神经元并调节局部微环境来补充缺失的神经元[36]。例如Esmaeilzade等[37]研究显示移植表皮神经嵴干细胞到阿尔茨海默病模型小鼠海马区域，可以分化为胆碱能神经元并改善阿尔茨海默病小鼠的记忆。目前通过神经干细胞移植来治疗以神经元的缺失为特征的神经退行性疾病已成为研究的热点，而如何调控神经干细胞向特定神经元分化成为了研究的难点。信号转导在神经干细胞的分化中起重要的作用，其中Wnt信号通路是调节神经干细胞增殖及分化的细胞外的重要因素[38]。在神经干细胞的体外培养过程中，加入有活性的Wnt3a蛋白可减少神经球的形成，促进神经干细胞向神经元及神经胶质细胞分化[39]。有研究表明成年大鼠室管膜下区来源的神经干细胞转染Wnt3a后，神经干细胞大部分向着神经元方向分化[40]。Wexler等[41]应用锂剂来激活Wnt通路，能够刺激成年小鼠体内海马前体细胞增殖，并能促进海马前体细胞分化为表达微管相关蛋白β-Ⅲ-Tubulin(Tuj1)的神经元。而近期有研究显示用含有Wnt3a的条件培养基培养小鼠的海马前体细胞，可以同时增加Ki67阳性的增殖状态的细胞和Tuj1阳性的已分化的细胞数量，但是两者的比例无明显变化，表明Wnt3a可以促进海马前体细胞的增殖与分化，但不能单独促进其分化，其机制可能与Wnt3a缩短了神经前体细胞的细胞周期有关[42]。Ping等[43]分离正常人及阿尔茨海默病患者皮层的胶质祖细胞，研究这些细胞分化为神经元的能力，发现相对于正常人，阿尔茨海默病患者的胶质祖细胞自我更新能力及神经发生能力明显下降，阿尔茨海默病患者的胶质祖细胞中有功能的β连环蛋白水平显著下降，而即将降解的磷酸化的β连环蛋白水平增高。由于神经干细胞来源及其取材较为复杂困难，近年来骨髓间充质干细胞移植治疗阿尔茨海默病受到人们的广泛关注。骨髓间充质干细胞移植到阿尔茨海默病小鼠模型的海马区域可以分化并补充缺失的海马神经元，还可以分泌多种蛋白质来阻止β淀粉样蛋白和tau蛋白介导的神经元死亡[44-45]。Wnt信号通路在调节骨髓间充质干细胞分化方面同样起着重要的作用。Wnt/β连环蛋白信号通路可以调节骨髓间充质干细胞的增殖及分化，骨髓间充质干细胞可以分化为有功能的神经元应用于脑损伤及神经退行性疾病的治疗[46-47]。另外，Wnt信号通路的过度激活可能会促进骨髓间充质干细胞的老化，故Wnt信号通路的激活要控制在一定的度才能促进骨髓间充质干细胞增殖与分化[48]。以上研究显示激活Wnt信号通路对多种干细胞及神经前体细胞的增殖与分化起调控作用，Wnt信号功能的缺失导致的神经形成能力的下降与阿尔茨海默病直接相关，为干细胞移植治疗神经退行性疾病提供了理论基础，但其具体机制有待进一步研究。"

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