van Leeuwen Lucie A G, Hoozemans Jeroen J M
Department of Pathology, VU University Medical Center, Neuroscience Campus Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
Acta Neuropathol. 2015 Apr;129(4):511-25. doi: 10.1007/s00401-015-1382-7. Epub 2015 Jan 25.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder for which no effective treatment is available. Increased insight into the disease mechanism in early stages of pathology is required for the development of a successful therapy. Over the years, numerous studies have shown that cell cycle proteins are expressed in neurons of AD patients. Traditionally, neurons are considered to be post-mitotic, which means that they permanently retract from the cell cycle. The expression of cell cycle proteins in adult neurons of AD patients has therefore been suggested to promote or even instigate pathomechanisms underlying AD. Interestingly, expression of cell cycle proteins is detected in post-mitotic neurons of healthy controls as well, albeit to a lesser extent than in AD patients. This indicates that cell cycle proteins may serve important physiological functions in differentiated neurons. Here, we provide an overview of studies that support a role of cell cycle proteins in DNA repair and neuroplasticity in post-mitotic neurons. Aberrant control of these processes could, in turn, contribute to cell cycle-mediated neurodegeneration. The balance between regenerative and degenerative effects of cell cycle proteins in post-mitotic neurons might change throughout the different stages of AD. In the early stages of AD pathology, cell cycle protein expression may primarily occur to aid in the repair of sublethal double-strand breaks in DNA. With the accumulation of pathology, cell cycle-mediated neuroplasticity and neurodegeneration may become more predominant. Understanding the physiological and pathophysiological role of cell cycle proteins in AD could give us more insight into the neurodegenerative process in AD.
阿尔茨海默病（AD）是最常见的神经退行性疾病，目前尚无有效的治疗方法。要开发成功的治疗方法，需要更深入地了解疾病病理早期的发病机制。多年来，大量研究表明，细胞周期蛋白在AD患者的神经元中表达。传统上，神经元被认为是终末有丝分裂后的，这意味着它们永久退出细胞周期。因此，有人认为AD患者成年神经元中细胞周期蛋白的表达会促进甚至引发AD的发病机制。有趣的是，在健康对照的终末有丝分裂后神经元中也检测到了细胞周期蛋白的表达，尽管程度低于AD患者。这表明细胞周期蛋白可能在分化的神经元中发挥重要的生理功能。在这里，我们概述了支持细胞周期蛋白在终末有丝分裂后神经元的DNA修复和神经可塑性中起作用的研究。对这些过程的异常控制反过来可能导致细胞周期介导的神经退行性变。在终末有丝分裂后神经元中，细胞周期蛋白的再生和退行性作用之间的平衡可能在AD的不同阶段发生变化。在AD病理的早期阶段，细胞周期蛋白表达可能主要是为了帮助修复DNA中的亚致死性双链断裂。随着病理的积累，细胞周期介导的神经可塑性和神经退行性变可能变得更加突出。了解细胞周期蛋白在AD中的生理和病理生理作用可以让我们更深入地了解AD中的神经退行性过程。
