高脂饮食介导Tau选择性剪接失衡并加重认知功能损伤
High-fat diet mediates tau-splicing imbalance and accelerates cognitive decline
秦冬冬 1李芳 1王志昊 1李易易 1余杭 1高锋 1王嘉贝 1王舰浩 1刘松燕 1陈洪玉 1李翔 1张茜 1王雅梅 1黄丽琴 1卢祖能1
作者信息
- 1. 430060 武汉大学人民医院神经内科、神经退行性疾病研究中心
- 折叠
摘要
目的 探讨高脂饮食(High-fat diet,HFD)对认知功能的影响及HFD促进阿尔茨海默病(Alzheimer's Disease,AD)发生的可能机制.方法 将8～10周龄的表达人Tau的转基因(Human Tau,hTau)AD小鼠(性别不限)随机分成2组,给予12周的HFD或正常饮食,通过水迷宫实验及情景恐惧实验评估其学习记忆能力,之后对脑组织进行逆转录-聚合酶链反应以评估Tau病变情况;将8～10周龄的hTau AD小鼠(性别不限)随机分成2组,立体定位注射丝氨酸精氨酸蛋白激酶2 N342A的慢病毒(Lentiviral-green fluorescent pro tein-serine/arginine-rich protein-specific kinase 2 N342A,LV-GFP-SRPK2 N342A)[不被剪切的SRPK2,可下调4个微管结合重复Tau(Four-repeat tauopathies,4R-Tau)]或LV-GFP病毒后连续12周给予HFD,通过水迷宫实验及情景恐惧实验评估其学习记忆能力,后对脑组织进行RT-PCR、免疫荧光染色以评估Tau病变情况.结果 HFD可干扰Tau的选择性剪切,使4R-Tau/3个微管结合重复Tau(Three-repeat tauopathies,3R-Tau)比例升高,从而加重Tau病变、促进认知功能障碍的发生;通过抑制SRPK2的剪切来调节4R-Tau与3R-Tau的比例,可使HFD的hTau AD小鼠认知功能得到改善,Tau病变减轻.结论 HFD可以介导的Tau的选择性剪接失调明显促进认知功能障碍的发生、加重Tau病变.
Abstract
Objective To explore the effect of high-fat diet(HFD)on tauopathies and the possible mechanism by which high-fat diet promotes the development of Alzheimer's disease.Methods The hTau AD mice at 8-10 weeks of age were randomly divided into two groups,and given a HFD or normal diet for 12 weeks.The learning memory ability were assessed by Morris Water Maze experiment and fear conditioning test,and the brain tissues were subjected to RT-PCR to assess tauopathies.To explore the role of SRPK2 in HFD-induced tauopathy,hTau AD mice at 8-10 weeks of age were randomly divided into two groups,and re-ceived stereotaxic injection of LV-GFP-SRPK2 N342A(non-sheared SRPK2,down-regulated 4R-Tau)or LV-GFP virus.Then we gave them a HFD for 12 weeks,assessed their learning memory ability by Morris Water Maze and fear conditioning test,and performed RT-PCR on brain tissue to assess tauopathies.Results HFD increases the 4R-Tau/3R-T au ratio,thereby exacerbating tauopathies and promoting cognitive impairment.Reducing 4R-Tau/3R-Tau ratio by inhibition of SRPK2 cleavage improved cognitive function and reduced tauopathies in hTau AD mice fed with HFD.Conclusion HFD mediates alternative splicing of MAPT gene,promotes cognitive impairment and exacerbates tauopathies in a mouse model of AD.
关键词
阿尔茨海默病/高脂饮食/Tau病变/Tau选择性剪接/丝氨酸精氨酸蛋白激酶2Key words
Alzheimer's disease/High-fat diet/Tauopathies/Alternative splicing/SRPK2引用本文复制引用
基金项目
国家自然科学基金青年科学基金(82101479)
国家重点研究计划(2021YFA1302400)
湖北省实验动物研究领域项目(2022DFE021)
武汉大学人民医院交叉创新人才项目(JCRCZN-2022-002)
出版年
2023
NETL
NSTL
维普
万方数据