Morris Gerwyn, Berk Michael
IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia; Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia.
Curr Alzheimer Res. 2016;13(8):853-61. doi: 10.2174/1567205013666160219113112.
Alzheimer`s disease is a progressive neurodegenerative illness characterized by the invariant existence of β-amyloid plaques and neurofibrillary tangles. Presently approved pharmaceutical approaches offer only marginal efficacy and as yet there is no effective treatment which reverses or arrests the disease. Thus far, drugs targeting any single aspect of disease pathology have proved to be a failure or at best provided very slight clinical benefit. The consistent failure of drugs targeting aspects of the Aβ cascade has questioned the causal role of this pathway. There is a growing appreciation that the pathogenesis of the illness is multifactorial with Amyloid Beta, Phosphorylated Tau (ptau), inflammation, mitochondrial dysfunction, calcium dyshomeostasis, heavy metal imbalances, and GSK-3 interact in a highly complex manner to provoke a selfsustaining spiraling cascade of pathology, driving disease progression. In the light of such complex pathology, the failure of drugs aimed a targeting single molecules is not surprising as such approaches are usually ineffective against other complex diseases with a multifactorial pathogenesis. Combination therapies or multi target drugs might be more effective in controlling such illnesses. The putative neuroprotective effects of Lithium are achieved via the positive modulation of numerous homeostatic mechanisms regulating autophagy, oxidative stress, inflammation, and mitochondrial dysfunction likely achieved by inhibiting GSK-3 and inositol-145 triphosphate. Data regarding efficacy in human trials and animal models of AD are mixed, but recent data using "microdose" lithium in mild cognitive impairment is encouraging, hence lithium could be a putative multi target treatment in these patients. However, additional well designed long-term trials are needed to confirm its efficacy and safety, given that long term use is necessary to achieve reasonable therapeutic benefit.
阿尔茨海默病是一种进行性神经退行性疾病，其特征是β-淀粉样蛋白斑块和神经原纤维缠结始终存在。目前获批的药物治疗方法疗效甚微，尚无有效治疗方法能逆转或阻止该疾病。迄今为止，针对疾病病理任何单一方面的药物都已证明是失败的，或者充其量只带来了非常轻微的临床益处。针对Aβ级联反应各方面的药物持续失败，这对该途径的因果作用提出了质疑。人们越来越认识到，该疾病的发病机制是多因素的，β-淀粉样蛋白、磷酸化tau蛋白（ptau）、炎症、线粒体功能障碍、钙稳态失调、重金属失衡以及糖原合成酶激酶-3以高度复杂的方式相互作用，引发自我维持的螺旋式病理级联反应，推动疾病进展。鉴于这种复杂的病理情况，针对单一分子的药物失败并不奇怪，因为此类方法通常对其他具有多因素发病机制的复杂疾病无效。联合疗法或多靶点药物可能在控制此类疾病方面更有效。锂的假定神经保护作用是通过对众多调节自噬、氧化应激、炎症和线粒体功能障碍的稳态机制进行正向调节实现的，这可能是通过抑制糖原合成酶激酶-3和肌醇-1,4,5-三磷酸来实现的。关于锂在阿尔茨海默病人体试验和动物模型中的疗效数据不一，但最近在轻度认知障碍中使用“微剂量”锂的数据令人鼓舞，因此锂可能是这些患者的一种假定多靶点治疗药物。然而，鉴于需要长期使用才能获得合理的治疗益处，还需要进行更多精心设计的长期试验来证实其疗效和安全性。
