Department of Pharmacology, School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith South DC, 1797, Australia.
J Neural Transm (Vienna). 2013 Jan;120(1):103-11. doi: 10.1007/s00702-012-0839-2. Epub 2012 Jun 13.
Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person's memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of β-amyloid (Aβ), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, early-onset form of AD, controversy exists between the "Baptists" (in favour of Aβ) and the "Tauists" (in favour of tau) as to which of these two protein dysfunctions occur at the earliest stages or are the most important contributors to the disease process in sporadic AD. However, more and more "non-amyloid" and "non-tau" causes have been proposed, including, glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. However, to get an insight into the ultimate cause of AD, and to prove that any drug target is valuable in AD, disease-relevant models giving insight into the pathogenic processes in AD are urgently needed. In the absence of a good animal model for sporadic AD, we propose in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD.
阿尔茨海默病（AD）是一种进行性神经退行性脑疾病，可导致患者的记忆和沟通能力以及日常活动能力逐渐下降。AD 的大脑病理学特征是广泛的神经元丧失，特别是胆碱能神经元丧失，由tau 蛋白（NFTs）组成的细胞内神经原纤维缠结和由β-淀粉样蛋白（Aβ）组成的细胞外斑块沉积，Aβ是淀粉样前体蛋白（APP）的裂解产物。这两种不溶性蛋白聚集体伴随着慢性炎症反应和广泛的氧化损伤。虽然 APP 表达或加工的失调似乎对家族性早发性 AD 很重要，但“浸礼派”（支持 Aβ）和“塔乌派”（支持 tau）之间存在争议，即这两种蛋白功能障碍中哪一种最早发生，或者对散发性 AD 的疾病进程最重要。然而，越来越多的“非淀粉样”和“非 tau”原因被提出，包括糖化、炎症、氧化应激和细胞周期失调。然而，要深入了解 AD 的根本原因，并证明任何药物靶点在 AD 中的价值，就迫切需要能够深入了解 AD 发病机制的疾病相关模型。在缺乏散发性 AD 良好动物模型的情况下，我们在本文中提出，源自 AD 患者皮肤成纤维细胞的诱导多能干细胞分化为胆碱能神经元，可能是散发性 AD 疾病建模和药物发现的有前途的新工具。
