Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
Neuron. 2021 May 19;109(10):1657-1674.e7. doi: 10.1016/j.neuron.2021.03.024. Epub 2021 Apr 7.
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3 or Tau/Aldh1l1-CreERT2/apoE4 mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.
载脂蛋白 E（APOE）基因是阿尔茨海默病最强的遗传风险因素，直接影响tau 病和 tau 介导的神经退行性变。APOE4 对这两个参数都有很强的有害影响。在大脑中，apoE 主要由星形胶质细胞和活化的小胶质细胞产生和分泌。每种形式的 apoE 在神经退行性变中的细胞特异性作用尚未确定。我们生成了 P301S Tau/Aldh1l1-CreERT2/apoE3 或 Tau/Aldh1l1-CreERT2/apoE4 小鼠。在 5.5 个月大时，即 tau 病理发生后，我们给予他莫昔芬或载体，并在 9.5 个月大时比较小鼠。去除星形胶质细胞 APOE4 可显著减少 tau 介导的神经退行性变，并减少磷酸化 tau（pTau）病理。单细胞 RNA 测序分析显示，所有细胞类型均发生了显著的基因表达变化，星形胶质细胞 APOE4 去除减少了神经元、少突胶质细胞、星形胶质细胞和小胶质细胞中与疾病相关的基因特征。去除星形胶质细胞 APOE4 减少了 tau 诱导的突触丢失和小胶质细胞对突触成分的吞噬作用，表明星形胶质细胞 apoE 在突触退化中起关键作用。
