Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Mol Neurodegener. 2023 Jun 20;18(1):39. doi: 10.1186/s13024-023-00624-5.
Alzheimer's disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD.
We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models.
Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34.
These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.
阿尔茨海默病（AD）是一种进行性和与年龄相关的神经退行性疾病，女性受其影响不成比例。然而，其潜在机制仍不清楚。此外，虽然已经研究了性别和 ApoE 基因型在 AD 中的相互作用，但用于了解这种相互作用的多组学研究有限。因此，我们应用系统生物学方法来研究 AD 的性别特异性分子网络。
我们通过多尺度网络分析整合了来自两个队列（MSBB 和 ROSMAP）的大规模人类死后大脑转录组数据，以确定具有性别二态表达模式和/或对性别之间 APOE 基因型有不同反应的关键驱动因素。使用死后人类大脑样本和 AD 小鼠模型中的基因扰动实验进一步研究 AD 中 top 性别特异性网络驱动因素的表达模式和功能相关性。
为每个性别确定了 AD 与对照相比的基因表达变化。为每个性别构建了基因共表达网络，以鉴定男性和女性之间共享或特定于每个性别的 AD 相关共表达基因模块。进一步确定关键网络调节剂作为 AD 发病机制和表现中性别差异的潜在驱动因素。LRP10 被确定为 AD 发病机制和表现中性别差异的顶级驱动因素。在人类 AD 大脑样本中进一步验证了 LRP10 在 mRNA 和蛋白质水平上的表达变化。EFAD 小鼠模型中的基因扰动实验表明，LRP10 以性别和 APOE 基因型特异性的方式对认知功能和 AD 病理产生不同的影响。LRP10 过表达（OE）E4FAD 雌性小鼠大脑中 LRP10 表达变化的综合图谱表明神经元和小胶质细胞是受影响最严重的细胞群体。从 LRP10 OE E4FAD 小鼠大脑的单细胞 RNA 测序（scRNA-seq）数据中鉴定的 LRP10 雌性特异性靶标在女性 AD 受试者的以 LRP10 为中心的子网络中显著富集，验证了 LRP10 作为女性 AD 的关键网络调节剂。通过酵母双杂交系统筛选鉴定了 8 个 LRP10 结合伴侣，LRP10 过表达减少了 LRP10 与一个结合伴侣 CD34 的结合。
这些发现为介导 AD 发病机制中性别差异的关键机制提供了深入了解，并将有助于为 AD 开发性别和 APOE 基因型特异性疗法。
