Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.
Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.
复制标题
DOI：
10.1186/s40478-023-01581-2
复制
发表时间：
2023-06-19
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
载脂蛋白（APOE）E4亚型是阿尔茨海默病的主要危险因素，并有助于脑老化过程中的代谢和神经病理学异常。为了深入了解APOE 4基因型是否与tau相关神经退行性变相关，我们培育了携带人源化APOE等位基因（APOE 2、APOE 3或APOE 4）的人P301 S突变tau转基因小鼠（PS19）。在死于瘫痪的衰老小鼠中，与APOE 4和APOE 2纯合子小鼠相比，APOE 3纯合子PS19小鼠的寿命最长（APOE 3> APOE 4 ~ APOE 2）。具有一个人APOE和一个小鼠Apoe等位基因的杂合子小鼠在寿命上没有表现出任何变化。在终末期，APOE 3和APOE 4纯合的PS19小鼠显示出相等水平的磷酸化tau负荷、炎症水平和心室容积。与这些队列相比，APOE 2纯合子PS19小鼠对选择性表位的磷酸化诱导较低，尽管效应大小较小且可变。尽管如此，APOE 2队列相对于APOE 3纯合子小鼠显示出较短的寿命。没有一个群组积累了在不溶性细胞部分中区室化的可感知水平的磷酸化tau。RNAseq分析表明，免疫基因表达的诱导在PS19小鼠中的所有APOE基因型之间是相当的。值得注意的是，APOE 4纯合小鼠显示出对应于阿尔茨海默病相关斑块诱导基因签名的转录物的额外诱导。在人类阿尔茨海默病脑组织中，我们发现磷酸化tau蛋白的高负荷与APOE 4基因型之间没有直接相关性。正如预期的那样，在APOE 4阳性阿尔茨海默病病例中，磷酸化tau蛋白负荷与淀粉样蛋白沉积之间存在强相关性。总的来说，我们的研究结果表明，APOE 3基因型可能赋予Tau病变一定的弹性，而APOE 4和APOE 2可能通过多种途径发挥作用，以增加Tau病变背景下的致病性。在线版本包含补充材料，可通过10.1186/s40478-023-01581-2获得。
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. The online version contains supplementary material available at 10.1186/s40478-023-01581-2.
登录
查看更多内容
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1084/jem.20202717
发表时间：
2021-09-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen Y;Colonna M
通讯作者：
Colonna M
影响因子：
11.1
作者：
Lumsden, Amanda L.;Mulugeta, Anwar;Hypponen, Elina
通讯作者：
Hypponen, Elina
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
3.8
作者：
Dörmer, P;Spitzer, E;Möller, W
通讯作者：
Möller, W