Dataset Information

Identification of Alzheimer's Disease Molecular Subtypes Based on Parallel Large-Scale Sequencing.

ABSTRACT: The incidence of Alzheimer's disease (AD) is constantly increasing as the older population grows, and no effective treatment is currently available. In this study, we focused on the identification of AD molecular subtypes to facilitate the development of effective drugs. AD sequencing data collected from the Gene Expression Omnibus (GEO) database were subjected to cluster sample analysis. Each sample module was then identified as a specific AD molecular subtype, and the biological processes and pathways were verified. The main long non-coding RNAs and transcription factors regulating each "typing pathway" and their potential mechanisms were determined using the RNAInter and TRRUST databases. Based on the marker genes of each "typing module," a classifier was developed for molecular typing of AD. According to the pathways involved, five sample clustering modules were identified (mitogen-activated protein kinase, synaptic, autophagy, forkhead box class O, and cell senescence), which may be regulated through multiple pathways. The classifier showed good classification performance, which may be useful for developing novel AD drugs and predicting their indications.

SUBMITTER: Ma M

PROVIDER: S-EPMC9112923 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Identification of Alzheimer's Disease Molecular Subtypes Based on Parallel Large-Scale Sequencing.

Ma Meigang M Liao Yuhan Y Huang Xiaohua X Zou Chun C Chen Liechun L Liang Lucong L Meng Youshi Y Wu Yuan Y Zou Donghua D

Frontiers in aging neuroscience 20220428

The incidence of Alzheimer's disease (AD) is constantly increasing as the older population grows, and no effective treatment is currently available. In this study, we focused on the identification of AD molecular subtypes to facilitate the development of effective drugs. AD sequencing data collected from the Gene Expression Omnibus (GEO) database were subjected to cluster sample analysis. Each sample module was then identified as a specific AD molecular subtype, and the biological processes and ...[more]

PMID: 35592696

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Project description:BackgroundProtein glycosylation has been confirmed to be involved in the pathological mechanisms of Alzheimer's disease (AD); however, there is still a lack of systematic analysis of the immune processes mediated by protein glycosylation-related genes (PGRGs) in AD.Materials and methodsTranscriptomic data of AD patients were obtained from the Gene Expression Omnibus database and divided into training and verification datasets. The core PGRGs of the training set were identified by weighted gene co-expression network analysis, and protein glycosylation-related subtypes in AD were identified based on k-means unsupervised clustering. Protein glycosylation scores and neuroinflammatory levels of different subtypes were compared, and functional enrichment analysis and drug prediction were performed based on the differentially expressed genes (DEGs) between the subtypes. A random forest model was used to select important DEGs as diagnostic markers between subtypes, and a line chart model was constructed and verified in other datasets. We evaluated the differences in immune cell infiltration between the subtypes through the single-sample gene set enrichment analysis, analyzed the correlation between core diagnostic markers and immune cells, and explored the expression regulation network of the core diagnostic markers.ResultsEight core PGRGs were differentially expressed between the training set and control samples. AD was divided into two subtypes with significantly different biological processes, such as vesicle-mediated transport in synapses and neuroactive ligand-receptor interactions. The high protein glycosylation subtype had a higher level of neuroinflammation. Riluzole and sulfasalazine were found to have potential clinical value in this subtype. A reliable construction line chart model was constructed based on nine diagnostic markers, and SERPINA3 was identified as the core diagnostic marker. There were significant differences in immune cell infiltration between the two subtypes. SERPINA3 was found to be closely related to immune cells, and the expression of SERPINA3 in AD was found to be regulated by a competing endogenous RNA network that involves eight long non-coding RNAs and seven microRNAs.ConclusionProtein glycosylation and its corresponding immune process play an important role in the occurrence and development of AD. Understanding the role of PGRGs in AD may provide a new potential therapeutic target for AD.

Project description:IntroductionAlzheimer's disease (AD) shows significant sex differences in prevalence and clinical manifestations, but the underlying molecular mechanisms remain unclear.MethodsThis study used a large-scale, single-cell transcriptomic atlas of the human prefrontal cortex to investigate sex-dependent molecular changes in AD. Our approach combined cell type-specific and sex-specific differential gene expression analysis, pathway enrichment, gene regulatory network construction, and cell-cell communication analysis to identify sex-dependent changes.ResultsWe found significant sex-specific gene expression patterns and pathway alterations in AD. Male astrocytes showed changes in cell death pathways, with RPTOR as a key regulator, while female astrocytes had alterations in Wnt signaling and cell cycle regulation. Cell-cell communication analysis uncovered sex-specific intercellular signaling patterns, with male-specific impacts on apoptosis-related signaling and female-specific alterations in Wnt and calcium signaling.DiscussionThis study reveals sex-dependent gene expression patterns, pathway alterations, and intercellular communication changes, suggesting the need for sex-specific approaches in AD research.HighlightsSingle-cell transcriptomics reveals significant sex-specific molecular signatures in Alzheimer's disease (AD). Male astrocytes show enhanced modulation of apoptotic and cell death pathways in AD; female astrocytes exhibit distinct alterations in Wnt signaling and cell-cycle regulation. Sex-dimorphic changes in mitochondrial gene expression are observed in excitatory neurons, suggesting divergent energy metabolism profiles may contribute to AD sex differences. RPTOR is identified as a key regulator of male-specific changes in astrocytes, implicating the mechanistic target of rapamycin pathway in sex-dependent AD pathology. New cell-cell communication analyses reveal sex-specific patterns of intercellular signaling, providing insights into how cellular interactions may differentially contribute to AD pathology in males and females.

Dataset Information

Identification of Alzheimer's Disease Molecular Subtypes Based on Parallel Large-Scale Sequencing.

Publications

Identification of Alzheimer's Disease Molecular Subtypes Based on Parallel Large-Scale Sequencing.

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