Kundu Payel, Stagaman Keaton, Kasschau Kristin, Holden Sarah, Shulzhenko Natalia, Sharpton Thomas J, Raber Jacob
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States.
Department of Microbiology, Oregon State University, Corvallis, OR, United States.
Front Behav Neurosci. 2022 Feb 8;16:791128. doi: 10.3389/fnbeh.2022.791128. eCollection 2022.
The gut microbiome and the gut brain axis are potential determinants of Alzheimer's disease (AD) etiology or severity and gut microbiota might coordinate with the gut-brain axis to regulate behavioral phenotypes in AD mouse models. Using 6-month-old human amyloid precursor protein (hAPP) knock-in (KI) mice, which contain the Swedish and Iberian mutations [APP NL-F ( )] or the Arctic mutation as third mutation [APP NL-G-F ( )], behavioral and cognitive performance is associated with the gut microbiome and APP genotype modulates this association. In this study, we determined the feasibility of behavioral testing of mice in a biosafety cabinet and whether stool from 6-month-old mice or crossed with human apoE4 targeted replacement mice is sufficient to induce behavioral phenotypes in 4-5 month-old germ-free C57BL/6J mice 4 weeks following inoculation. We also compared the behavioral phenotypes of the recipient mice with that of the donor mice. Finally, we assessed cortical Aβ levels and analyzed the gut microbiome in the recipient mice. These results show that it is feasible to behaviorally test germ-free mice inside a biosafety cabinet. However, the host genotype was critical in modulating the pattern of induced behavioral phenotypes as compared to those seen in the genotype- and sex-match donor mice. Male mice that received stool from and donor genotypes tended to have lower body weight as compared to wild type, an effect not observed among donor mice. Additionally, recipient males, but not females, showed impaired object recognition. Insoluble Aβ40 levels were detected in and recipient mice. Recipients of but not , donor mice carried cortical insoluble Aβ40 levels that positively correlated with activity levels on the first and second day of open field testing. For recipient mice, the interaction between donor genotype and several behavioral scores predicted gut microbiome alpha-diversity. Similarly, two behavioral performance scores predicted microbiome composition in recipient mice, but this association was dependent on the donor genotype. These data suggest that genotypes of the donor and recipient might need to be considered for developing novel therapeutic strategies targeting the gut microbiome in AD and other neurodegenerative disorders.
肠道微生物群和肠脑轴是阿尔茨海默病（AD）病因或严重程度的潜在决定因素，并且肠道微生物群可能与肠脑轴协同作用，以调节AD小鼠模型中的行为表型。使用6个月大的携带瑞典和伊比利亚突变[APP NL-F( )]或作为第三个突变的北极突变[APP NL-G-F( )]的人淀粉样前体蛋白（hAPP）基因敲入（KI）小鼠，行为和认知表现与肠道微生物群相关，且APP基因型可调节这种关联。在本研究中，我们确定了在生物安全柜中对小鼠进行行为测试的可行性，以及6个月大小鼠或与人类载脂蛋白E4靶向替换小鼠杂交的小鼠的粪便是否足以在接种4周后在4-5个月大的无菌C57BL/6J小鼠中诱导行为表型。我们还比较了受体小鼠与供体小鼠的行为表型。最后，我们评估了受体小鼠的皮质Aβ水平，并分析了其肠道微生物群。这些结果表明，在生物安全柜内对无菌小鼠进行行为测试是可行的。然而，与基因型和性别匹配的供体小鼠相比，宿主基因型在调节诱导的行为表型模式方面至关重要。接受来自 和 供体基因型粪便的雄性小鼠与野生型相比体重往往较低，而在供体小鼠中未观察到这种效应。此外， 受体雄性小鼠（而非雌性小鼠）表现出物体识别受损。在 和 受体小鼠中检测到不溶性Aβ40水平。接受 而非 供体小鼠粪便的受体小鼠，其皮质不溶性Aβ40水平与旷场测试第一天和第二天的活动水平呈正相关。对于受体小鼠，供体基因型与几个行为评分之间的相互作用可预测肠道微生物群的α多样性。同样，两个行为表现评分可预测受体小鼠的微生物群组成，但这种关联取决于供体基因型。这些数据表明，在开发针对AD和其他神经退行性疾病肠道微生物群的新型治疗策略时，可能需要考虑供体和受体的基因型。
