Table_1_Transcriptomic analysis reveals sex-specific patterns in the hippocampus in Alzheimer’s disease.xlsx

BackgroundThe hippocampus, vital for memory and learning, is among the first brain regions affected in Alzheimer’s Disease (AD) and exhibits adult neurogenesis. Women face twice the risk of developing AD compare to men, making it crucial to understand sex differences in hippocampal function for comprehending AD susceptibility.MethodsWe conducted a comprehensive analysis of bulk mRNA postmortem samples from the whole hippocampus (GSE48350, GSE5281) and its CA1 and CA3 subfields (GSE29378). Our aim was to perform a comparative molecular signatures analysis, investigating sex-specific differences and similarities in the hippocampus and its subfields in AD. This involved comparing the gene expression profiles among: (a) male controls (M-controls) vs. female controls (F-controls), (b) females with AD (F-AD) vs. F-controls, (c) males with AD (M-AD) vs. M-controls, and (d) M-AD vs. F-AD. Furthermore, we identified AD susceptibility genes interacting with key targets of menopause hormone replacement drugs, specifically the ESR1 and ESR2 genes, along with GPER1.ResultsThe hippocampal analysis revealed contrasting patterns between M-AD vs. M-controls and F-AD vs. F-controls, as well as M-controls vs. F-controls. Notably, BACE1, a key enzyme linked to amyloid-beta production in AD pathology, was found to be upregulated in M-controls compared to F-controls in both CA1 and CA3 hippocampal subfields. In M-AD vs. M-controls, the GABAergic synapse was downregulated, and the Estrogen signaling pathway was upregulated in both subfields, unlike in F-AD vs. F-controls. Analysis of the whole hippocampus also revealed upregulation of the GABAergic synapse in F-AD vs. F-controls. While direct comparison of M-AD vs. F-AD, revealed a small upregulation of the ESR1 gene in the CA1 subfield of males. Conversely, F-AD vs. F-controls exhibited downregulation of the Dopaminergic synapse in both subfields, while the Calcium signaling pathway showed mixed regulation, being upregulated in CA1 but downregulated in CA3, unlike in M-AD vs. M-controls. The upregulated Estrogen signaling pathway in M-AD, suggests a compensatory response to neurodegenerative specifically in males with AD. Our results also identified potential susceptibility genes interacting with ESR1 and ESR2, including MAPK1, IGF1, AKT1, TP53 and CD44.ConclusionThese findings underscore the importance of sex-specific disease mechanisms in AD pathogenesis. Region-specific analysis offers a more detailed examination of localized changes in the hippocampus, enabling to capture sex-specific molecular patterns in AD susceptibility and progression.

背景海马体，作为记忆和学习的关键区域，在阿尔茨海默病（AD）早期受到影响，并表现出成人神经发生。女性患AD的风险是男性的两倍，因此理解海马体功能的性别差异对于阐明AD易感性至关重要。方法我们对全海马体及其CA1和CA3亚区的尸检mRNA样本（GSE48350，GSE5281，GSE29378）进行了全面分析。我们的目标是进行分子特征分析比较，探讨AD中海马体及其亚区性别特异性差异和相似性。这包括比较以下几组之间的基因表达谱：（a）男性对照（M-对照）与女性对照（F-对照），（b）患有AD的女性（F-AD）与F-对照，（c）患有AD的男性（M-AD）与M-对照，以及（d）M-AD与F-AD。此外，我们还确定了与更年期激素替代药物的关键靶点（ESR1和ESR2基因）以及GPER1相互作用的AD易感基因。结果海马体分析揭示了M-AD与M-对照、F-AD与F-对照以及M-对照与F-对照之间的对比模式。值得注意的是，BACE1，一种与AD病理中淀粉样蛋白-β产生相关的关键酶，在CA1和CA3海马体亚区中在M-对照中比F-对照上调。在M-AD与M-对照中，GABA能突触下调，而在F-AD与F-对照中，雌激素信号通路在上调，这与F-AD与F-对照不同。对整个海马体的分析还揭示了F-AD与F-对照中GABA能突触的上调。而M-AD与F-AD的直接比较显示，在男性CA1亚区中ESR1基因略有上调。相反，F-AD与F-对照在两个亚区中Dopaminergic突触下调，而钙信号通路表现出混合调节，CA1中上调，而CA3中下调，这与M-AD与M-对照不同。M-AD中上调的雌激素信号通路表明，这是对神经退行性病变的一种补偿性反应，特别是在AD男性患者中。我们的结果还确定了与ESR1和ESR2相互作用的潜在易感基因，包括MAPK1、IGF1、AKT1、TP53和CD44。结论这些发现强调了在AD发病机制中性别特异性疾病机制的重要性。区域特异性分析提供了对海马体局部变化的更详细检查，使能够捕捉AD易感和进展中的性别特异性分子模式。