Webber Kate M, Casadesus Gemma, Zhu Xiongwei, Obrenovich Mark E, Atwood Craig S, Perry George, Bowen Richard L, Smith Mark A
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106. USA.
Curr Pharm Des. 2006;12(6):691-7. doi: 10.2174/138161206775474305.
Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.
人们已经提出了几种假说，试图解释阿尔茨海默病（AD）的发病机制，包括涉及淀粉样蛋白沉积、tau蛋白磷酸化、氧化应激、金属离子失调和炎症的理论。有力证据表明，每一种机制都对疾病发病机制有影响，尽管这些机制都不会导致AD病程中出现的所有下游变化。因此，我们和其他人已经开始寻找一个早于AD中已知特征的致病因素，它可能是病理生理级联反应的根本启动因素。在这方面，我们提出，在AD期间海马中易发生变性的神经元中发生的细胞周期失调是一个潜在的致病因素，它将引发所有已知的病理事件。支持AD病因中细胞周期控制改变的神经元变化包括细胞周期标志物的异位表达、细胞器运动以及包括tau蛋白磷酸化在内的细胞骨架改变。鉴于细胞周期重新进入的早期且可能具有破坏性的后果，我们齐心协力阐明驱动AD中异常有丝分裂重新进入的起始因素。由于AD存在性别偏见，我们怀疑绝经后激素和雄激素可能参与其中，考虑到这一点，在本综述中我们特别关注促性腺激素。如果促性腺激素确实是驱动有丝分裂的力量，针对促性腺激素的治疗干预措施既可以预防目前无症状患者的疾病，也可以阻止甚至逆转目前患病患者的疾病。
