Revelation of Pivotal Genes Pertinent to Alzheimer’s Pathogenesis: A Methodical Evaluation of 32 GEO Datasets

Gns, Hema Sree; Rajalekshmi, Saraswathy Ganesan; Burri, Raghunadha Reddy

doi:10.1007/s12031-021-01919-2

Cited by 10 publications

(6 citation statements)

References 78 publications

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“…This observation reflects that when neurons are subjected to high stress, the nearby astrocytes become reactivated and migrate towards these neurons to support their survival (55). Meanwhile, consistent with previous transcriptional studies in AD (56–59), ENC1 , CALM2 , CCK, RGS4 were downregulated in the pseudo-spots covering highly stressed Ex ( Fig. 3G ).…”

Section: Resultssupporting

confidence: 92%

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution

Gong,

Haeri,

Zhang

et al. 2024

Preprint

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Aging significantly elevates the risk for Alzheimer’s disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

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Section: Resultssupporting

confidence: 92%

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution

Gong,

Haeri,

Zhang

et al. 2024

Preprint

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“…A study by Zhang et al also showed that ENC1 played an important role in the mitogen-activated protein kinase ( MEK )/extracellular signal-regulated kinase ( ERK ) pathway to promote cervical cancer ( 18 ). Evidence has shown that ENC1 also was one of the key genes involved in the pathogenesis of Alzheimer's disease ( 19 ). He et al found that upregulated ENC1 predicts unfavorable prognosis and correlates with immune infiltration in endometrial cancer ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of ENC1 in gastrointestinal tumors: Bioinformatics analysis based on a public gene database

Liu¹,

Liu²,

Li³

2023

J Gastrointest Oncol

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Background To investigate the expression characteristics of ectodermal-neural cortex 1 ( ENC1 ) in gastrointestinal tumors and its potential value in judging the prognosis of patient survival. Methods RNA sequence (RNA-seq) data and patient survival data related to stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD) in gastric cancer and colon cancer from The Cancer Genome Atlas (TCGA) were downloaded for expression difference analysis and Cox survival regression analysis. A Kaplan–Meier (KM) survival curve was plotted to analyze the tumor invasion level of patients with different ENC1 expression levels, and the main influencing pathways of ENC1 were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein network analysis. Results The data of 405 STAD samples and 494 COAD clinical samples of TCGA were analyzed, and it was found that the expression of ENC1 in tumor tissues of patients with both types of cancer was significantly higher than that in normal tissues, with Log 2 fold change values of 1.97 and 2.06, respectively, P<0.001. Cox analysis revealed that the high expression of ENC1 was not significantly correlated with the prognosis and survival time of patients with gastric cancer and patients with colon cancer: overall survival (OS) hazard ratio (HR): 1.039, 95% confidence interval (CI): 0.890–1.213, P=0.627 for gastric cancer, OS HR: 0.886, 95% CI: 0.702–1.111, P=0.306 for colon cancer. KEGG pathway enrichment analysis of gene ENC1 revealed that ENC1 was mainly involved in neuroactive ligand-receptor interaction. The high expression of ENC1 was associated with various immune cells and different T cells such as basophils, CD4 + memory T cells, CD4 + TEM, and MV endothelial cells in gastric and colon cancers. The results of ENC1 protein interaction network analysis suggested that ENC1 may be involved in regulating neurite formation and neural crest cell differentiation. Conclusions ENC1 expression is elevated in both gastric and colon cancers, and ENC1 is associated with various immune cells and different T cells such as basophils, CD4 + memory T cells, CD4 + TEM, and MV endothelial cells in both gastric and colon cancers, but ENC1 does not affect the survival and prognosis of patients.

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“…Several of these 29 genes have been previously reported to be associated with Alzheimer's Disease: overexpression of ANGPT1* has been found to increase amyloid beta secretion (Peng et al, 2020) whilst CLEC4G suppresses amyloid beta (Kizuka et al, 2015), and increased levels of ENC1 (Gns et al, 2022;White et al, 2017) and NPTX2 (Belbin et al, 2020;Libiger et al, 2021;Shao et al, 2020;Xiao et al, 2017) Note: Pearson's r values for the correlation between brain-g associations and brain-gene expression component profiles. Note that these are for linear associations using the absolute gene-expression component scores.…”

Section: Associations Between G and Individual Genesmentioning

confidence: 99%

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

Moodie,

Harris,

Harris

et al. 2024

Human Brain Mapping

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Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region‐to‐region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell‐signalling/modification and transcription factors. We validate these patterns out‐of‐sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta‐analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|β| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health‐related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

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Revelation of Pivotal Genes Pertinent to Alzheimer’s Pathogenesis: A Methodical Evaluation of 32 GEO Datasets

Cited by 10 publications

References 78 publications

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution

Expression and clinical significance of ENC1 in gastrointestinal tumors: Bioinformatics analysis based on a public gene database

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

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