APP N端在阿尔茨海默病病理中的多维调控作用及靶向治疗潜力  

The multifaceted role of APP N-terminus in Alzheimer's disease pathogenesis and therapeutic targeting

作　　者：谭俊 陈江 齐晓岚[1] TAN Jun;CHEN Jiang;QI Xiaolan(Key Laboratory of Medical Biology,Guizhou Medical University,Guiyang 550004,Guizhou,China;Key Laboratory of Endemic and Ethnic Diseases,Ministry of Education,Guiyang 550004,Guizhou,China)

机构地区：[1]贵州医科大学分子生物学重点实验室,贵州贵阳550004 [2]贵州医科大学地方病与少数民族疾病教育部重点实验室,贵州贵阳550004

出　　处：《贵州医科大学学报》2025年第3期313-324,共12页Journal of Guizhou Medical University

基　　金：国家自然科学基金(82060211,82460263);贵州医科大学高层次人才项目(YJ19017);贵州省科技厅计划项目(黔科合基础-ZK[2023]一般301);贵州省科技人才合作平台项目(CXTD[2023]003)。

摘　　要：阿尔茨海默病(Alzheimer's disease,AD)的病理过程涉及多个机制,包括β-淀粉样蛋白(amyloid-β,Aβ)积聚、Tau蛋白磷酸化、神经炎症以及突触丧失。淀粉样前体蛋白(amyloid precursor protein,APP)作为Aβ的前体,APP N端不仅调控Aβ的生成,还在Tau病理、炎症反应和突触功能失调中扮演关键角色。APP N端由E1结构域、KPI域和AcD组成,调节多个病理通路,推动AD的进展。近年来研究揭示,APP N端的多功能性使其成为AD治疗的新兴靶点。靶向N端的策略,如6KApoE肽和AV-1959D疫苗,显示出在多靶点干预中的潜力,但仍面临血脑屏障穿透性和脱靶效应的挑战。未来的研究将聚焦APP N端在AD多病理网络中的作用,结合多组学技术、类器官模型及人工智能辅助药物设计,推动精准治疗策略的发展。Objective Alzheimer's disease(AD)pathogenesis involves multiple mechanisms,including amyloid-β(Aβ)accumulation,Tau phosphorylation,neuroinflammation,and synaptic loss.As the precursor of Aβ,the N-terminus of amyloid precursor protein(APP)not only regulates Aβgeneration but also plays a key role in Tau pathology,inflammatory responses,and synaptic dysfunction.The N-terminus of APP consists of the E1 domain,KPI domain,and AcD,which regulate multiple pathological pathways and drive AD progression.Recent studies have revealed that the multifunctionality of the APP N-terminus makes it an emerging therapeutic target for AD.Targeting the N-terminus,with strategies such as the 6KApoE peptide and AV-1959D vaccine,shows potential in multi-target intervention,though challenges such as blood-brain barrier penetration and off-target effects remain.Future research will focus on the role of the APP N-terminus in AD's multi-pathological network,combining multi-omics technologies,organoid models,and AI-assisted drug design to advance precision therapeutic strategies.

关 键 词：阿尔茨海默病 APP N端 Aβ生成 Tau病理 靶向治疗 

分 类 号：R749.16[医药卫生—神经病学与精神病学]