载脂蛋白E与阿尔茨海默病:风险、机制和治疗  

Apolipoprotein E and Alzheimer’s Disease:Risk,Mechanisms,and Treatment

作　　者：陈是燏 林志成 应佳芹 李婉怡 刘志涛 方甜园 周钰愉 张楚霞 谢凯 徐淑君[1] 李丽萍 CHEN Shi-Yu;LIN Zhi-Cheng;YING Jia-Qin;LI Wan-Yi;LIU Zhi-Tao;FANG Tian-Yuan;ZHOU Yu-Yu;ZHANG Chu-Xia;XIE Kai;XU Shu-Jun;LI Li-Ping(Department of Physiology and Pharmacology,Health Science Center,Ningbo University,Ningbo 315211,China;Rehabilitative Department,the First Affiliated Hospital of Ningbo University,Ningbo 315211,China;Department of Science and Education,Ningbo Rehabilitation Hospital,Ningbo 315040,China)

机构地区：[1]宁波大学医学部生理与病理学科,宁波315211 [2]宁波大学附属第一医院康复科,宁波315211 [3]宁波市康复医院科教科,宁波315040

出　　处：《生物化学与生物物理进展》2025年第3期569-591,共23页Progress In Biochemistry and Biophysics

基　　金：浙江省自然科学基金(LY23H090004);浙江省省属高校基本科研业务费专项(SJLY2023008);宁波市自然科学基金(2023J068,2022J035);国家自然科学基金(82001155);宁波市重点研发计划(2023Z173);浙江省医药卫生科技计划(2022KY1144);浙江省中医药科技计划(2023ZL162);浙江省大学生科技创新活动计划(新苗人才计划)(2024R405A069);宁波市鄞州区农业与社会发展类项目(2022AS025);宁波大学大学生科技创新计划(SRIP)(2024SRIP1904,2024SRIP1905);高等学校学科创新引智基地(111计划)(D16013)资助。

摘　　要：阿尔茨海默病(Alzheimer’s disease,AD)是痴呆中最常见疾病类型,随着人口老龄化的不断加剧,其患病率正在迅速增加。在越来越多的遗传风险因素中,载脂蛋白E(apolipoprotein E,ApoE)是最普遍和最强的风险因素,在AD病例中约占3/4。ApoE是中枢神经系统脂质和胆固醇代谢的关键蛋白质,有三种不同亚型:ApoE2、ApoE3和ApoE4,其中ApoE4是AD发病的高风险因素。ApoE4不仅影响神经胶质细胞中脂质的外排和分布,同时还影响神经元的脂质代谢,导致脂质稳态失衡。ApoE参与淀粉样前体蛋白(APP)的加工,促进早期β淀粉样蛋白(Aβ)的产生和斑块沉积。ApoE4还降低Tau蛋白溶解度,促使Tau异常磷酸化和聚集,导致神经原纤维缠结(NFTs),且表达ApoE4的脑区更易受到Tau扩散的影响。ApoE4通过激活NF-κB炎症通路,使小胶质细胞和星形胶质细胞转变为促炎表型,分泌促炎因子和氧化介质,诱发神经炎症。总而言之,ApoE通过影响Aβ斑块、Tau病理、神经炎症、神经可塑性及血脑屏障(BBB)等多途径参与AD神经病理,共同助推疾病进展。抗ApoE4抗体可以降低Aβ斑块的形成和神经炎症;二甲双胍、雷帕霉素、依诺肝素、二十二碳六烯酸(DHA)和他莫西芬等已批准使用的药物,显示出具有降低ApoE4和改善AD病理的潜力;使用反义寡核苷酸(ASO)和双链干扰小RNA(siRNA)技术的基因疗法,通过降低ApoE4的表达,可减缓AD病理。腺相关病毒(AAV)介导的ApoE2基因疗法通过在室管膜中表达ApoE2,以中和ApoE4的负面影响。中药白藜芦醇和水景苷通过ApoE修饰的脂质体纳米给药系统递送,提高了药物的BBB穿透性,为AD治疗提供了新手段。此外,通过靶向ApoE4与低密度脂蛋白受体(LDLR)、低密度脂蛋白受体相关蛋白1(LRP1)受体的相互作用,可以间接调节ApoE4的表达水平,为AD治疗提供了新的视角。本文梳理近年来ApoE及其亚型在AD发病机制中的作用,并综述了抗ApoE�Alzheimer’s disease(AD)is the most common form of dementia,and its prevalence is rapidly increasing with the aging population.Among the growing number of genetic risk factors,apolipoprotein E(ApoE)is the most prevalent and strongest risk factor,accounting for nearly three-quarters of AD cases.ApoE is a key protein involved in lipids and cholesterol metabolism in the central nervous system.There are three subtypes of ApoE:ApoE2,ApoE3,and ApoE4,among which ApoE4 is a high-risk factor for the incidence of AD.ApoE4 not only affects lipid efflux and distribution in glial cells,but also affects the lipid metabolism in neurons,resulting in the imbalance of lipid homeostasis.ApoE plays a role in the processing of amyloid precursor protein(APP),which is associated with the early production of amyloidβ-protein(Aβ)and plaque deposition.ApoE4 also reduces the solubility of Tau protein,which contributes to promoting the aberrant phosphorylation and the aggregation of Tau,and resulting in neurofibrillary tangles(NFTs).Moreover,brain regions expressing ApoE4 are more susceptible to Tau diffusion.Furthermore,ApoE4 has been demonstrated to activate the NF-κB inflammatory pathway,convert microglia and astrocytes into the pro-inflammatory phenotypes,secrete proinflammatory factors and oxidative mediators,and induce neuroinflammation.Altogether,ApoE participates in AD neuropathology through multiple pathways such as Aβplaque,Tau pathology,neuroinflammation,neuroplasticity and blood-brain barrier,which all jointly promotes the progression of the disease.It has been demonstrated that anti-ApoE4 antibodies can reduce the formation of Aβplaques and neuroinflammation.The repurposing of metformin,rapamycin,enoxaparin,DHA,and tamoxifen have been shown to reduce the expression of ApoE4 protein and ameliorate AD pathology.Gene therapies utilising antisense oligonucleotides(ASO)and double-stranded interfering small RNA(siRNA)has been proved to be effective technologies to reduce ApoE4 expression and mitigate AD pathology.Adeno-associat

关 键 词：阿尔茨海默病 载脂蛋白E 脂质稳态 小胶质细胞 神经炎症 神经胶质细胞 

分 类 号：R3-74[医药卫生—基础医学]