{"title":"确定与阿尔茨海默病相关的性别特异性基因、转录因子和途径的综合方法。","authors":"","doi":"10.1016/j.nbd.2024.106605","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Age represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions.</p></div><div><h3>Methods</h3><p>The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity.</p></div><div><h3>Results</h3><p>We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (<span><span>https://bioinfo.cipf.es/metafun-ad/</span><svg><path></path></svg></span>).</p></div><div><h3>Conclusion</h3><p>Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002055/pdfft?md5=6c2723ca06b3b591899eff5a86016312&pid=1-s2.0-S0969996124002055-main.pdf","citationCount":"0","resultStr":"{\"title\":\"An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer's disease\",\"authors\":\"\",\"doi\":\"10.1016/j.nbd.2024.106605\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Age represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions.</p></div><div><h3>Methods</h3><p>The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity.</p></div><div><h3>Results</h3><p>We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (<span><span>https://bioinfo.cipf.es/metafun-ad/</span><svg><path></path></svg></span>).</p></div><div><h3>Conclusion</h3><p>Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. 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引用次数: 0
摘要
背景:年龄是阿尔茨海默病(AD)发病的一个重要风险因素;然而,最近的研究表明,性别在阿尔茨海默病的几个特征中起着影响作用。了解性别对与阿尔茨海默病相关的特定分子机制的影响仍然是制定有针对性的治疗干预措施所面临的一项重要挑战:通过系统性回顾,首先选择了 2002 年至 2021 年期间与性别有关的 AD 转录组研究,重点关注受 AD 影响的主要脑区--皮层(CT)和海马(HP)。然后对每项研究进行了差异表达分析,并进行了两项组织特异性荟萃分析。由于CT存在与SDID相关的显著改变,因此我们以CT为重点,进行了全面的功能表征:通过蛋白质-蛋白质网络交互作用和过度代表性分析来探索生物过程和通路,并通过VIPER分析来估计转录因子的活性:我们从基因表达总库(GEO)中选择了8项CT研究和5项HP研究进行组织特异性荟萃分析。与 CT 相比,我们发现 SDID 中有 389 个基因发生了明显改变。一般来说,女性AD患者的受影响基因多于男性;我们根据这些基因在女性和男性AD患者中的表达情况将其分为六个亚组。在功能分析过程中,只有子集 I(女性 AD 患者中被抑制的基因)显示出显著的结果。与男性AD患者相比,女性AD患者在与神经递质(谷氨酸和GABA)、蛋白质折叠、Aβ聚集和积累相关的突触和通路的调节和组织相关的生物过程中表现出更明显的损伤。这些发现可以部分解释为什么我们观察到女性注意力缺失症患者的认知能力下降更为明显。最后,我们发现 23 个转录因子根据性别具有不同的激活模式,其中一些首次与注意力缺失症相关。这项研究的所有结果都可以通过开放的网络资源Metafun-AD(https://bioinfo.cipf.es/metafun-ad/)获取:我们的荟萃分析表明,女性和男性患者的注意力缺失症相关机制存在差异。这些基于性别的差异将成为新假说的基础,并将对精准医学产生重大影响,改善注意力缺失症患者的诊断和临床疗效。
An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer's disease
Background
Age represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions.
Methods
The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity.
Results
We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/).
Conclusion
Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.
期刊介绍:
Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.