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

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 protein-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。

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 received 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-Tau 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.