Dataset Information

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

ABSTRACT: Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.

SUBMITTER: Beck JS

PROVIDER: S-EPMC9667180 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

Beck John S JS Madaj Zachary Z Cheema Calvin T CT Kara Betul B Bennett David A DA Schneider Julie A JA Gordon Marcia N MN Ginsberg Stephen D SD Mufson Elliott J EJ Counts Scott E SE

Cerebral cortex (New York, N.Y. : 1991) 20221101 22

Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this prob ...[more]

PMID: 35076713

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Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of toxic misfolded proteins, which are believed to have propagated from disease-specific epicenters through their corresponding large-scale structural networks in the brain. Although previous cross-sectional studies have identified potential AD-associated epicenters and corresponding brain networks, it is unclear whether these networks are associated with disease progression. Hence, this study aims to identify the most vulnerable epicenters and corresponding large-scale structural networks involved in the early stages of AD and to evaluate its associations with multiple cognitive domains using longitudinal study design. Annual neuropsychological and MRI assessments were obtained from 23 patients with AD, 37 patients with amnestic mild cognitive impairment (MCI), and 33 healthy controls (HC) for 3 years. Candidate epicenters were identified as regions with faster decline rate in the gray matter volume (GMV) in patients with MCI who progressed to AD as compared to those regions in patients without progression. These epicenters were then further used as pre-defined regions of interest to map the synchronized degeneration network (SDN) in HCs. Spatial similarity, network preference and clinical association analyses were used to evaluate the specific roles of the identified SDNs. Our results demonstrated that the hippocampus and posterior cingulate cortex (PCC) were the most vulnerable AD-associated epicenters. The corresponding PCC-SDN showed significant spatial association with the patterns of GMV atrophy rate in each patient group and the overlap of these patterns was more evident in the advanced stages of the disease. Furthermore, individuals with a higher GMV atrophy rate of the PCC-SDN also showed faster decline in multiple cognitive domains. In conclusion, our findings suggest the PCC and hippocampus are two vulnerable regions involved early in AD pathophysiology. However, the PCC-SDN, but not hippocampus-SDN, was more closely associated with AD progression. These results may provide insight into the pathophysiology of AD from large-scale network perspective.

Project description:ObjectiveTo investigate the differential expression gene modules and hub genes associated with Alzheimer's disease (AD) by weighted gene co-expression network analysis (WGCNA) and annotate the biological functions of these modules.MethodsWe downloaded transcriptome sequencing data from the GEO database, and according to the correlation of the genes, a gene co-expression network was constructed with the parameter setting of β=8 and a correlation coefficient threshold of 0.85. Pearson correlation test was used to calculate the correlation between the module genes and clinical traits to screen the gene modules significantly associated with AD and identify the hub genes according to the connectivity within modules. GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules. A cell model of AD was established in SH-SY5Y cells by Aβ1-42 treatment, and the mRNA expression levels of the hub genes were compared between the Aβ1-42-treated cells and the control cells.ResultsTen gene co-expression modules were constructed based on the correlations of gene expression, in which the brown (r=0.66, P < 0.001) and turquoise modules (r=-0.68, P < 0.001) were significantly correlated with the AD group. Forty-eight genes were identified as the hub genes in the co-expression network. Function annotation revealed that the genes in both modules were mainly enriched in DNA damage and repair pathways and metabolism-related pathways. Differential expression analysis of the genes revealed that the genes DNASE1, TEKT2 and MTSS1L were highly expressed while ACP2, LANCL2 and GMPR2 were lowly expressed in AD group. The results of cell experiment confirmed the up-regulation of DNASE1, TEKT2 and MTSS1L genes and the down-regulation of ACP2, LANCL2, and GMPR2 in Aβ1-42-treated SH-SY5Y cells (P < 0.01).ConclusionThe brown and turquoise modules are closely correlated with AD. The hub genes including MTSS1L, GMPR2, ACP2, ACTG1 and LANCL2 selected from the modules may participate in AD pathogenesis by regulating DNA damage and repair.

Dataset Information

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

Publications

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

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