Wingo Thomas S, Yang Jingjing, Fan Wen, Min Canon Se, Gerasimov Ekaterina Sergeevna, Lori Adriana, Logsdon Benjamin, Yao Bing, Seyfried Nicholas T, Lah James J, Levey Allan I, Boyle Patricia A, Schneider Julia A, De Jager Philip L, Bennett David A, Wingo Aliza P
1Department of Neurology, Emory University School of Medicine, Atlanta, GA USA.
2Department of Human Genetics, Emory University School of Medicine, Atlanta, GA USA.
NPJ Genom Med. 2020 Feb 6;5:6. doi: 10.1038/s41525-019-0113-8. eCollection 2020.
Late-life depression is associated with an increased risk for dementia but we have limited knowledge of the molecular mechanisms underlying this association. Here we investigated whether brain microRNAs, important posttranscriptional regulators of gene expression, contribute to this association. Late-life depressive symptoms were assessed annually in 300 participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of 7 years. Participants underwent annual cognitive testing, clinical assessment of cognitive status, and uniform neuropathologic examination after death. microRNAs were profiled from the prefrontal cortex using NanoString platform in the discovery cohort and small RNA sequencing in the replication cohort. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for the potential confounding factors. Four brain microRNAs were associated with late-life depressive symptoms at adjusted < 0.05: miR-484, miR-26b-5p, miR-30d-5p, and miR-197-3p. Lower expression levels of these miRNAs were associated having greater depressive symptoms. Furthermore, lower levels of miR-484 and miR-197-3p were associated with faster decline of cognition over time. Moreover, lower miR-484 level was associated with higher probability of having Alzheimer's dementia. Importantly, the associations between miR-484 and depressive symptoms and Alzheimer's dementia, respectively, were replicated in an independent cohort. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of synaptic plasticity. This study identified four brain microRNAs associated with late-life depressive symptoms assessed longitudinally. In addition, we found a molecular connection between late-life depression and dementia through miR-484.
晚年抑郁症与患痴呆症的风险增加有关，但我们对这种关联背后的分子机制了解有限。在这里，我们研究了大脑微小RNA（基因表达的重要转录后调节因子）是否促成了这种关联。在宗教团体研究和拉什记忆与衰老项目的300名参与者中，每年评估晚年抑郁症状，平均持续7年。参与者每年接受认知测试、认知状态的临床评估，并在死后进行统一的神经病理学检查。在发现队列中使用NanoString平台，在复制队列中使用小RNA测序对前额叶皮质的微小RNA进行分析。使用线性混合模型对潜在混杂因素进行调整，对晚年抑郁症状进行了全基因组微小RNA关联研究。在调整后P < 0.05时，四种大脑微小RNA与晚年抑郁症状相关：miR-484、miR-26b-5p、miR-30d-5p和miR-197-3p。这些微小RNA的较低表达水平与更严重的抑郁症状相关。此外，miR-484和miR-197-3p的较低水平与认知能力随时间的更快下降相关。此外，miR-484水平较低与患阿尔茨海默病痴呆症的可能性较高相关。重要的是，miR-484与抑郁症状和阿尔茨海默病痴呆症之间的关联分别在一个独立队列中得到了验证。最后，miR-484的预测靶点在一个涉及突触传递和突触可塑性调节的大脑蛋白质共表达模块中富集。这项研究确定了四种与纵向评估的晚年抑郁症状相关的大脑微小RNA。此外，我们通过miR-484发现了晚年抑郁症和痴呆症之间的分子联系。
