酪氨酸磷酸化调节激酶1A在阿尔茨海默病中的作用和机制

The role of dual specificity tyrosine-phosphorylation-regulated kinase 1A in the pathogenesis of Alzheimer's disease

阿尔茨海默病(Alzheimer’s disease,AD)是一种以学习记忆减退和认知功能障碍为特征的中枢神经系统退行性疾病,主要病理学改变为β-淀粉样蛋白(amyloidβ-protein,Aβ)沉积和Tau蛋白异常磷酸化,但其病因及发病机制目前尚未完全阐明。双底物特异性酪氨酸磷酸化调节激酶1A(dual specificity tyrosine-phosphorylation-regulated kinase 1A,DYRK1A)是一种在进化中高度保守的蛋白激酶,与大脑发育异常、神经退行性改变、认知障碍和早发性AD相关。DYRK1A可通过磷酸化多种底物的丝氨酸或苏氨酸残基促进AD疾病中老年斑形成、神经纤维缠结、氧化应激和神经炎症反应,因此DYRK1A可能是防治AD的重要靶点。本文将对DYRK1A的结构、分布、功能及其在AD发病中的作用进行综述,旨在为AD的研究和治疗提供新的思路。

Alzheimer's disease(AD)is a chronic degenerative disease of the central nervous system,characterized byβ-amyloid deposition and abnormal phosphorylation of Tau protein,while its etiology and pathogenesis have not been fully elucidated.The most common presentation of AD is of an elderly individual with progressive problems of memory impairment,cognitive dysfunction,mental symptoms,and loss of living ability.Dual-specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)is a highly evolutionary conserved protein kinase,which is related to retardation,neurodegeneration,severe cognitive impairment,and early onset AD.Compelling data have implicated that DYRK1A phosphorylates a variety of substrates on serine or threonine residues,thereby regulating the dfferent cellular processes involved in brain development and function.Thus,DYRK1A might be a promising target for the prevention and treatment of AD,as it is implicated in the formation of senile plaques,neurofibrillary tangles,oxidative stress injury and inflammatory responses.In this paper,we reviews the structure,distribution,and function of DYRK1A,as well as its role in the pathogenesis of AD,in order to provide a theoretical basis for the treatment of AD.