铁离子失衡在阿尔茨海默病发病机制中的作用研究进展

Developments in the Role of Iron Imbalance in the Pathogenesis of Alzheimer's Disease

铁离子负荷与阿尔茨海默病(AD)的发生和发展密切相关。虽然Aβ沉积形成的老年斑(SPs)和tau蛋白过度磷酸化形成的神经原纤维缠结(NFTs)是AD发病的两个主要病理特征,但临床对SPs和NFTs的诱导因素仍有不同的看法,至今尚未明确。本文重点探讨了铁离子稳态失衡与AD发病机制的关系,对其最新研究进展进行了归纳和总结。包括以下几个方面:首先,随着年龄的增长,大脑不同区域的铁沉积可能会损害正常的认知功能和行为。其次,铁离子失衡和氧化应激通过激活β-或γ-分泌酶和抑制α-分泌酶共同或独立地促进Aβ的过度产生,还通过激活糖原合成酶激酶3β(GSK-3β)、细胞周期蛋白依赖性蛋白激酶5(CDK5)等蛋白激酶和抑制蛋白磷酸酶2A(PP2A)引起tau蛋白的过度磷酸化。由铁离子不平衡引起的改变会反过来加剧铁离子的分布和沉积。铁离子失衡和Aβ/tau蛋白异常之间的恶性循环最终可能促进AD发展。再次,铁离子超负荷还可直接或间接破坏细胞器,引起内质网应激、线粒体和自噬功能障碍,可引起或加重Aβ和tau蛋白的聚集/积累,损害突触功能。同时,铁代谢异常通过Fenton反应产生羟基自由基,引发氧化应激反应,破坏细胞脂质、蛋白质和DNA的结构和功能,最终导致细胞死亡。最后,鉴于传统铁螯合剂长期应用的局限性和不良反应,α-硫辛酸(LA)和乳铁蛋白(LF)作为自合成的靶向小分子,在阻断Aβ聚集、tau蛋白过度磷酸化和神经元损伤方面显示出非常好的生物活性,有望推向临床。因此铁靶向治疗策略有望成为AD治疗的新方向。

Iron load is closely associated with the initiation and progression of Alzheimer's disease(AD).Although age-dependent deposition ofβ-amyloid(Aβ)in senile plaques(SPs),and neurofibrillary tangles(NFTs)formed by accumulation of hyperphosphorylated tau proteins are two major pathological features of AD,there are still many different views on the inducing factors of SPs and NFTs.We reviewed the new developments in the relationship between imbalance of brain iron homeostasis and the pathogenesis of AD,with a summary presented as follows:(1)Age-related iron deposits in different brain regions may damage normal cognitive function and behavior.(2)Iron imbalance and oxidative stress may together or independently promote Aβoverproduction by activatingβ-orγ-secretases and inhibitingα-secretase,and also cause tau hyperphosphorylation by activating protein kinases,such as glycogen synthase kinase-3β,cyclin-dependent protein kinase-5,and inhibiting protein phosphatase 2A.Iron imbalance-induced changes will in turn aggravate brain iron deposition and distribution.The vicious circle between iron imbalance and Aβ/tau anomalies may eventually lead to AD.(3)Iron overload may also directly or indirectly injure organelles,causing endoplasmic reticulum stress,mitochondrial and autophagy dysfunction,and damaging synaptic function via inducing or aggravating the aggregation or accumulation of Aβand tau.At the same time,hydroxyl radicals produced via the Fenton reaction associated with abnormal iron metabolism,may trigger oxidative stress,destroy the structure and function of cell lipids,protein and DNA,eventually leading to cell death.(4)Given the limitations and side effects of long-term application of traditional iron chelators,alpha-lipoic acid and lactoferrin as self-synthesized naturally small molecules,are expected to be applied to clinical practice,for they have shown very intriguing biological activities in blocking Aβ-aggregation,tau hyperphosphorylation and neuronal damage.We believe that iron-targeted therapies are a promising direction for the treatment of AD.