Guerini, F. R. | bioRxiv Science

bioRxiv2023

An integrated approach to identify sex-specific genes, transcription factors, and pathways in Alzheimer's disease

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/556293v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@4a60d7org.highwire.dtl.DTLVardef@11bd7eborg.highwire.dtl.DTLVardef@fc9b69org.highwire.dtl.DTLVardef@3f239f_HPS_FORMAT_FIGEXP M_FIG C_FIG BackgroundAge represents a significant risk factor for the development of Alzheimers 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. MethodsThe 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. ResultsWe 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, A{beta} 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/). ConclusionOur 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. HighlightsO_LIFemale AD patients possess more affected genes than male AD patients. C_LIO_LI389 genes from the sex-based differential impact on disease comparison significantly impact the cerebral cortex and suggest a more significant effect on cognitive function in female AD patients. C_LIO_LIThe cluster of repressed genes in female AD patients functionally impacts glutamate and GABA neurotransmitters and A{beta} deposition. C_LIO_LIFemale AD patients exhibit several transcription factors with significantly different activity patterns compared to male AD patients. C_LIO_LIThis work includes Metafun-AD, an open and interactive web tool to explore all generated data and results. C_LI

neuroscience↗

bioRxiv2023

The role of microRNAs to understand sex-based differences in Alzheimer's disease

BackgroundThe incidence of Alzheimers disease (AD) - the most frequent cause of dementia - is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment. MethodsA systematic review identified five studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms. ResultsMeta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and twenty-two miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process. ConclusionsSex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information. HighlightsO_LIDeregulation of miRNA expression profiles occurs in a tissue- and sex-specific manner in AD patients C_LIO_LIMeta-analysis of blood samples revealed a partial overlapping pattern of altered miRNA expression in female and male AD patients C_LIO_LIFunctional enrichment based on AD-associated miRNA expression profiles in blood samples reveals sex-based differences: RNA splicing and translation in female AD patients and ubiquitination, regulation of different kinase activities, and apoptotic process in male AD patients C_LIO_LILinks between AD development and miRNA expression in brain tissue also demonstrate the influence of sex C_LI Plain English SummaryAlzheimers disease (AD) - a neurodegenerative disease mainly affecting older patients - is characterized by cognitive deterioration, memory loss, and progressive incapacitation in daily activities. While AD affects almost twice as many females as males, and cognitive deterioration and brain atrophy develop more rapidly in females, the biological causes of these differences remain poorly understood. MicroRNAs (miRNAs) regulate gene expression and impact a wide variety of biological processes; therefore, studying the differential expression of miRNAs in female and male AD patients could contribute to a better understanding of the disease. We reviewed studies of miRNA expression in female and male AD patients and integrated results using a meta-analysis methodology and then identified those genes regulated by the altered miRNAs to establish an association with biological processes. We found sixteen (females) and twenty-two (males) miRNAs altered in the blood of AD patients. Functional enrichment revealed sex-based differences in the affected altered biological processes - protein modification and degradation and cell death in male AD patients and RNA processing in female AD patients. A similar analysis in the brains of AD patients revealed six (females) and four (males) miRNAs with altered expression; however, our analysis failed to highlight any specifically altered biological processes. Overall, we highlight the sex-based differential expression of miRNAs (and biological processes affected) in the blood and brain of AD patients.

neuroscience↗