Comorbidity between Alzheimer's disease and Major Depression: a behavioural and transcriptomic characterization study in mice

Background: Major Depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown. Method: In this regard, we investigated the cognitive and emotional behavioural responses in 3- (n=16 per group) and 6-month-old (n=14 per group) in APP/PSEN1-Tg mutant mice, before beta-amyloid plaques were detected in comparison with non-transgenic mice. Then, we studied the deregulation of genes and pathways in prefrontal cortex, striatum, hippocampus and amygdala of mice at both ages, using transcriptomic and functional data analysis. Results: We found that depressive-like and anxiety-like behaviours, as well as memory impairments are already present at 3-month-old APP/PSEN1-Tg mutant mice together with the deregulation of several genes such as Ciart, Chrm5, Aldh1a, Grin3b, Nr1d1 and Mc4r, and gene sets, including components of the circadian rhythms, electronic transport chain, neuroinflammation and neurotransmission. Then, we extended these results to human data performing GSEA analysis using DisGeNET database, which is specific for diseases and disease-related phenotypes and provides translational support for common deregulated gene sets related to MD and AD. Conclusion: The present study shed further light on the genetic bases shared between MD and AD, illustrating a wide characterization from the behavioural to transcriptomic level in APP/PSEN1-Tg mutant mouse model. These findings could indicate that late MD could be an early manifestation of AD. Transcriptomic analysis comparison between APP/PSEN1 and non-transgenic mice in four different brain regions at two different ages.背景：重度抑郁症（Major Depression, MD）是人群中最为常见的精神疾病，同时被认为是阿尔茨海默病（Alzheimer's disease, AD）的前驱阶段。尽管两种疾病均具有较强的遗传基础，但二者共有的转录组特征仍未明确。方法：为此，我们在β淀粉样蛋白斑块（beta-amyloid plaques）尚未被检出的阶段，对比APP/PSEN1-Tg突变小鼠（3月龄，每组n=16；6月龄，每组n=14）与非转基因小鼠的认知与情绪行为反应。随后，我们通过转录组学与功能数据分析，探究了两个年龄组小鼠前额叶皮层（prefrontal cortex）、纹状体（striatum）、海马体（hippocampus）及杏仁核（amygdala）内的基因与通路失调情况。结果：我们发现，3月龄APP/PSEN1-Tg突变小鼠已出现抑郁样、焦虑样行为及记忆损伤，同时伴随Ciart、Chrm5、Aldh1a、Grin3b、Nr1d1及Mc4r等多个基因，以及包含昼夜节律、电子传递链、神经炎症与神经递质传递相关组分在内的基因集的失调。随后，我们将上述研究结果拓展至人类数据集，使用专为疾病及疾病相关表型开发的DisGeNET数据库开展基因集富集分析（Gene Set Enrichment Analysis, GSEA），为与MD和AD相关的共失调基因集提供了转化研究依据。结论：本研究进一步阐明了MD与AD共享的遗传基础，从行为学层面至转录组学层面全面表征了APP/PSEN1-Tg突变小鼠模型。本研究结果提示，晚发性MD可能是AD的早期临床表现。本研究同时开展了APP/PSEN1转基因小鼠与非转基因小鼠在四个不同脑区、两个不同年龄阶段的转录组对比分析。