Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Mol Neurodegener. 2019 Dec 20;14(1):47. doi: 10.1186/s13024-019-0352-2.
Alzheimer's disease (AD) is a fatal neurodegenerative disease. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared to the common APOE3. Importantly, female (♀) APOE4 carriers have a greater risk for developing AD and an increased rate of cognitive decline compared to male (♂) APOE4 carriers. While recent evidence demonstrates that AD, APOE genotype, and sex affect the gut microbiome (GM), how APOE genotype and sex interact to affect the GM in AD remains unknown.
This study analyzes the GM of 4-month (4 M) ♂ and ♀ E3FAD and E4FAD mice, transgenic mice that overproduce amyloid-β 42 (Aβ42) and express human APOE3 or APOE4. Fecal microbiotas were analyzed using high-throughput sequencing of 16S ribosomal RNA gene amplicons and clustered into operational taxonomic units (OTU). Microbial diversity of the EFAD GM was compared across APOE, sex and stratified by APOE + sex, resulting in 4-cohorts (♂E3FAD, ♀E3FAD, ♂E4FAD and ♀E4FAD). Permutational multivariate analysis of variance (PERMANOVA) evaluated differences in bacterial communities between cohorts and the effects of APOE + sex. Mann-Whitney tests and machine-learning algorithms identified differentially abundant taxa associated with APOE + sex.
Significant differences in the EFAD GM were associated with APOE genotype and sex. Stratification by APOE + sex revealed that APOE-associated differences were exhibited in ♂EFAD and ♀EFAD mice, and sex-associated differences were exhibited in E3FAD and E4FAD mice. Specifically, the relative abundance of bacteria from the genera Prevotella and Ruminococcus was significantly higher in ♀E4FAD compared to ♀E3FAD, while the relative abundance of Sutterella was significantly higher in ♂E4FAD compared to ♂E3FAD. Based on 29 OTUs identified by the machine-learning algorithms, heatmap analysis revealed significant clustering of ♀E4FAD separate from other cohorts.
The results demonstrate that the 4 M EFAD GM is modulated by APOE + sex. Importantly, the effect of APOE4 on the EFAD GM is modulated by sex, a pattern similar to the greater AD pathology associated with ♀E4FAD. While this study demonstrates the importance of interactive effects of APOE + sex on the GM in young AD transgenic mice, changes associated with the development of pathology remain to be defined.
阿尔茨海默病（AD）是一种致命的神经退行性疾病。APOE4 是 AD 的最大遗传风险因素，与常见的 APOE3 相比，风险增加了 15 倍。重要的是，与携带 APOE3 的男性相比，携带 APOE4 的女性发生 AD 的风险更高，认知能力下降的速度也更快。虽然最近的证据表明 AD、APOE 基因型和性别会影响肠道微生物组（GM），但 APOE 基因型和性别如何相互作用影响 AD 中的 GM 仍不清楚。
本研究分析了 4 个月（4M）♂和♀E3FAD 和 E4FAD 小鼠的 GM，这些转基因小鼠过度产生淀粉样蛋白-β42（Aβ42）并表达人 APOE3 或 APOE4。使用 16S 核糖体 RNA 基因扩增子的高通量测序分析粪便微生物群，并聚类为操作分类单元（OTU）。比较 APOE、性别和按 APOE+性别分层的 EFAD GM 微生物多样性，结果产生 4 个队列（♂E3FAD、♀E3FAD、♂E4FAD 和♀E4FAD）。通过置换多元方差分析（PERMANOVA）评估细菌群落之间的差异，并评估 APOE+性别对细菌群落的影响。曼-惠特尼检验和机器学习算法确定与 APOE+性别相关的差异丰度分类群。
EFAD GM 的显著差异与 APOE 基因型和性别有关。按 APOE+性别分层显示，APOE 相关差异在♂EFAD 和♀EFAD 小鼠中表现出来，而性别相关差异在 E3FAD 和 E4FAD 小鼠中表现出来。具体而言，与♀E3FAD 相比，♀E4FAD 中普雷沃氏菌属和真杆菌属细菌的相对丰度显著更高，而♂E4FAD 中 Sutterella 属细菌的相对丰度显著更高。基于机器学习算法确定的 29 个 OTU，热图分析显示♀E4FAD 与其他队列明显聚类。
研究结果表明，APOE+性别调节 4M EFAD GM。重要的是，APOE4 对 EFAD GM 的影响受性别调节，这与♀E4FAD 中与 AD 相关的更大病理表现相似。虽然本研究表明 APOE+性别对年轻 AD 转基因小鼠 GM 的交互作用的重要性，但与发病机制发展相关的变化仍有待确定。
