人源化 APOE 基因型影响寿命，而不依赖于 P301S 小鼠 tau 病模型中的 tau 聚集。
Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.
机构信息
Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.
Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA.
出版信息
Acta Neuropathol Commun. 2023 Jun 19;11(1):99. doi: 10.1186/s40478-023-01581-2.
Apolipoprotein (APOE) E4 isoform is a major risk factor of Alzheimer's disease and contributes to metabolic and neuropathological abnormalities during brain aging. To provide insights into whether APOE4 genotype is related to tau-associated neurodegeneration, we have generated human P301S mutant tau transgenic mice (PS19) that carry humanized APOE alleles (APOE2, APOE3 or APOE4). In aging mice that succumbed to paralysis, PS19 mice homozygous for APOE3 had the longest lifespan when compared to APOE4 and APOE2 homozygous mice (APOE3 > APOE4 ~ APOE2). Heterozygous mice with one human APOE and one mouse Apoe allele did not show any variations in lifespan. At end-stage, PS19 mice homozygous for APOE3 and APOE4 showed equivalent levels of phosphorylated tau burden, inflammation levels and ventricular volumes. Compared to these cohorts, PS19 mice homozygous for APOE2 showed lower induction of phosphorylation on selective epitopes, though the effect sizes were small and variable. In spite of this, the APOE2 cohort showed shorter lifespan relative to APOE3 homozygous mice. None of the cohorts accumulated appreciable levels of phosphorylated tau compartmentalized in the insoluble cell fraction. RNAseq analysis showed that the induction of immune gene expression was comparable across all the APOE genotypes in PS19 mice. Notably, the APOE4 homozygous mice showed additional induction of transcripts corresponding to the Alzheimer's disease-related plaque-induced gene signature. In human Alzheimer's disease brain tissues, we found no direct correlation between higher burden of phosphorylated tau and APOE4 genotype. As expected, there was a strong correlation between phosphorylated tau burden with amyloid deposition in APOE4-positive Alzheimer's disease cases. Overall, our results indicate that APOE3 genotype may confer some resilience to tauopathy, while APOE4 and APOE2 may act through multiple pathways to increase the pathogenicity in the context of tauopathy.
载脂蛋白（APOE）E4 异构体是阿尔茨海默病的主要风险因素，并导致大脑衰老过程中的代谢和神经病理学异常。为了深入了解 APOE4 基因型是否与 tau 相关的神经退行性变有关，我们生成了携带人源化 APOE 等位基因（APOE2、APOE3 或 APOE4）的人 P301S 突变 tau 转基因小鼠（PS19）。在因瘫痪而死亡的老年小鼠中，与 APOE4 和 APOE2 纯合子小鼠相比，APOE3 纯合子 PS19 小鼠的寿命最长（APOE3>APOE4~APOE2）。携带一个人源 APOE 和一个鼠源性 Apoe 等位基因的杂合子小鼠的寿命没有任何差异。在终末期，APOE3 和 APOE4 纯合的 PS19 小鼠的磷酸化 tau 负担、炎症水平和脑室容积水平相当。与这些队列相比，APOE2 纯合的 PS19 小鼠显示出选择性表位磷酸化的诱导水平较低，尽管效应大小较小且变化较大。尽管如此，与 APOE3 纯合子小鼠相比，APOE2 队列的寿命较短。没有一个队列积累了可检测到的磷酸化 tau 与不溶性细胞部分隔室化的水平。RNAseq 分析表明，在 PS19 小鼠中，所有 APOE 基因型的免疫基因表达诱导相当。值得注意的是，APOE4 纯合小鼠还额外诱导了与阿尔茨海默病相关斑块诱导基因特征相对应的转录本。在人类阿尔茨海默病脑组织中，我们发现磷酸化 tau 负担与 APOE4 基因型之间没有直接相关性。正如预期的那样，在 APOE4 阳性阿尔茨海默病病例中，磷酸化 tau 负担与淀粉样蛋白沉积之间存在很强的相关性。总体而言，我们的结果表明，APOE3 基因型可能为 tau 病提供一定的抗性，而 APOE4 和 APOE2 可能通过多种途径在 tau 病的背景下增加致病性。
Zotero 插件