Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, 32224, USA.
Nat Commun. 2018 Oct 22;9(1):4388. doi: 10.1038/s41467-018-06783-0.
Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.
载脂蛋白 E (APOE) ε4 等位基因是晚发性阿尔茨海默病最强的遗传风险因素，主要通过调节淀粉样蛋白-β 病理学。APOE ε4 还被证明会加重tau 转基因小鼠模型中的神经退行性变和神经炎症。为了进一步评估 APOE 基因型与 tau 病理学的存在和严重程度的关系，我们通过腺相关病毒基因传递方法在人 APOE 靶向替换小鼠中表达人 tau。我们发现表达 APOE ε2/ε2 的小鼠中出现更多的过度磷酸化 tau 物种、tau 聚集物和行为异常。我们还表明，在人类中，APOE ε2 等位基因与进行性核上性麻痹 (PSP) 病例大脑中的 tau 病理学增加有关。最后，我们使用两个系列经病理证实的 PSP 和皮质基底节变性病例，确定了 APOE ε2/ε2 基因型与 tau 病风险之间的关联。我们的数据表明，APOE ε2 状态可能会影响 tau 病的风险和进展。
