Unearthing of Key Genes Driving the Pathogenesis of Alzheimer’s Disease via Bioinformatics

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with unelucidated molecular pathogenesis. Herein, we aimed to identify potential hub genes governing the pathogenesis of AD. The AD datasets of GSE118553 and GSE131617 were collected from the NCBI GEO database. The weighted gene coexpression network analysis (WGCNA), differential gene expression analysis, and functional enrichment analysis were performed to reveal the hub genes and verify their role in AD. Hub genes were validated by machine learning algorithms. We identified modules and their corresponding hub genes from the temporal cortex (TC), frontal cortex (FC), entorhinal cortex (EC), and cerebellum (CE). We obtained 33, 42, 42, and 41 hub genes in modules associated with AD in TC, FC, EC, and CE tissues, respectively. Significant differences were recorded in the expression levels of hub genes between AD and the control group in the TC and EC tissues (P < 0.05). The differences in the expressions of FCGRT, SLC1A3, PTN, PTPRZ1, and PON2 in the FC and CE tissues among the AD and control groups were significant (P < 0.05). The expression levels of PLXNB1, GRAMD3, and GJA1 were statistically significant between the Braak NFT stages of AD. Overall, our study uncovered genes that may be involved in AD pathogenesis and revealed their potential for the development of AD biomarkers and appropriate AD therapeutics targets.

Genomic architecture of Autism Spectrum Disorder from comprehensive whole-genome sequence annotation

“…While the overlaps between ASD and conditions such as ADHD, obsessive-compulsive disorder (OCD), intellectual disability (ID), and epilepsy have been well-established (Viscidi et al, 2013; Kushki et al, 2019; Thurm et al, 2019), potential links between ASD and other disorders are less clear. Interestingly, several of our novel ASD-associated genes have tentative links with neurodegenerative disorders, such as Alzheimer’s disease (AD)— NR4A 2 (Jesús et al, 2021; Moon et al, 2019), ATP2B2 (Brendel et al, 2014), EIF4E (Li et al, 2004; Ghosh et al, 2020), EBF3 (Rao et al, 2018), MARK2 (Segu et al, 2008; Gu et al, 2013; Zhou et al, 2019), EPOR (Brettschneider et al, 2006; Hernández et al, 2017), G3BP1 (Martin et al, 2013; Silva et al, 2019), PLXNB1 (Yu et al, 2018; Zhao et al, 2021), APBB1 (McLoughlin and Miller, 2008; Zeidán-Chuliá et al, 2014; Probst et al, 2020), and ANP32A (Chai et al, 2017, 2018; Podvin et al, 2020). The link between ASD and neurodegenerative disease may also extend to X-linked genes; for example, variants in RAB39B have been linked to both (Mata et al, 2015; Woodbury-Smith et al, 2017).…”

ADAM10 pharmacological inhibition modifies the expression of components of the dopaminergic system

“…Moreover, it has been recently evidenced that MAOB levels were higher in the frontal cortex, hippocampus CA1 and entorhinal cortex of AD brain than in controls, that the enzyme is a γ-secretase-associated protein and that intraneuronal Aβ 42 levels correlated with MAOB levels [62]. Importantly, this molecular and genetic evidence has recently been reinforced by bioinformatics studies using microarray datasets that have detected higher expression of MAOA, MAOB and COMT in the brain of AD patients when compared to control individuals [63-65] and modified COMT expression in the hippocampus of AD patients [66]. Furthermore, a meta analytic review has also reported a significant increase in hippocampal MAOB expression in AD [67].…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…PTPRZ1 SNPs significantly associating with the risk to develop schizophrenia have been reported ( Buxbaum et al, 2008 ) but the gene’s link with Alzheimer’s Disease thus far is based on expression levels of RPTPζ isoforms and of its ligand pleiotrophin in postmortem material ( Zhao et al, 2021 ). Because schizophrenia-associated genes represent promising candidates for predicting antidepressant efficacy, Su and others have tested five PTPRZ1 SNPs for an association with anxiety remission status in two Chinese cohorts that were stratified for the medication received, but correction for multiple testing aborted the potential associations ( Su et al, 2021a ).…”