Cerpa Waldo, Dinamarca Margarita C, Inestrosa Nibaldo C
Centro de Regulación Celular y Patología Joaquín V Luco (CRCP), Millennium Institute (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Curr Alzheimer Res. 2008 Jun;5(3):233-43. doi: 10.2174/156720508784533321.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A characteristic of AD is the accumulation of plaques in the brain of AD patients, and theses plaques mainly consist of aggregates of amyloid beta-peptide (Abeta). All converging lines of evidence suggest that progressive accumulation of the Abeta plays a central role in the genesis of Alzheimer's disease and it was long understood that Abeta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. This process could be modulated by molecular chaperones which inhibit or accelerate the amyloid formation. The enzyme Acetylcholinesterase (AChE) induces Abeta fibrils formation, forming a stable complex highly neurotoxic. On the other hand, laminin inhibit the Abeta fibrils formation and depolymerizate Abeta fibrils also. Over the past decade, data have emerged from the use of several sources of Abeta (synthetic, cell culture, transgenic mice and human brain) to suggest that intermediate species called Abeta oligomers are also injurious. Accumulating evidence suggests that soluble forms of Abeta are indeed the proximate effectors of synapse loss and neuronal injury. On the other hand, the member of the Wnt signaling pathway, beta-catenin was markedly reduced in AD patients carrying autosomal dominant PS-1. Also, neurons incubated with Abeta revealed a significant dose-dependent decrease in the levels of cytosolic beta-catenin an effect which was reversed in cells co-incubated with increasing concentrations of lithium, an activator of Wnt signaling pathway. Wnt signaling blocks the behavioural impairments induced by hippocampal injection of Abeta, therefore the activation of Wnt signaling protects against the Abeta neurotoxicity. Here we review recent progress about Abeta structure and function, from the formation of amyloid fibrils and some molecular chaperones which modulate the amyloidogenesic process to synaptic damage induce by Abeta oligomers.
阿尔茨海默病（AD）是老年人口不断增长的情况下最常见的神经退行性疾病。AD的一个特征是AD患者大脑中出现斑块堆积，这些斑块主要由β-淀粉样肽（Aβ）聚集体组成。所有证据都表明，Aβ的逐渐积累在阿尔茨海默病的发病机制中起核心作用，长期以来人们认为Aβ必须组装成细胞外淀粉样纤维才能发挥其细胞毒性作用。这个过程可以被抑制或加速淀粉样蛋白形成的分子伴侣调节。乙酰胆碱酯酶（AChE）诱导Aβ纤维形成，形成一种高度神经毒性的稳定复合物。另一方面，层粘连蛋白抑制Aβ纤维形成并使Aβ纤维解聚。在过去十年中，使用多种Aβ来源（合成的、细胞培养的、转基因小鼠和人脑）的数据表明，被称为Aβ寡聚体的中间物种也具有危害性。越来越多的证据表明，可溶性Aβ形式确实是突触丧失和神经元损伤的直接效应物。另一方面，在携带常染色体显性PS-1的AD患者中，Wnt信号通路成员β-连环蛋白明显减少。此外，用Aβ孵育的神经元显示胞质β-连环蛋白水平呈显著剂量依赖性下降，在与浓度不断增加的锂（Wnt信号通路激活剂）共同孵育的细胞中，这种效应被逆转。Wnt信号通路可阻断海马注射Aβ诱导的行为障碍，因此Wnt信号通路的激活可防止Aβ神经毒性。在这里，我们综述了关于Aβ结构和功能的最新进展，从淀粉样纤维的形成以及一些调节淀粉样蛋白生成过程的分子伴侣到Aβ寡聚体诱导的突触损伤。
