Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus

Abstract

In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alzheimer's disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, functional pathway enrichment and protein-protein interaction (PPI) network analyses were performed on the DEGs. The extended genes with PPI to the DEGs were obtained. Finally, the DEGs and the extended genes were ranked using the convergent functional genomics method. Eighty DEGs with q \ 0.1, including 67 downregulated and 13 upregulated genes, were identified. In the pathway enrichment analysis, the 80 DEGs were significantly enriched in one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, GABAergic synapses, and 22 Gene Ontology terms. These genes were mainly involved in neuron, synaptic signaling and transmission, and vesicle metabolism. These processes are all linked to the pathological features of AD, demonstrating that the GABAergic system, neurons, and synaptic function might be affected in AD. In the PPI network, 180 extended genes were obtained, and the hub gene occupied in the most central position was CDC42. After prioritizing the candidate genes, 12 genes, including five DEGs (ITGB5, RPH3A, GNAS, THY1, and SEPT6) and seven extended genes (JUN, GDI1, GNAI2, NEK6, UBE2D3, CDC42EP4, and ERCC3), were found highly relevant to the progression of AD and recognized as promising biomarkers for its early diagnosis.

Neuronal–Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer’s Disease: Gene Ontology and Lithium Pathways

“…In this context, to explore the molecular aspects underlying the complex changes observed in AD, a number of genome-wide expression profiling experiments were performed in hippocampal tissues from AD patients (Elsheikh et al, 2019;Andrews et al, 2020), including functional pathway enrichment analyses with gene ontology terms of expression profiling. The most relevant GO categories in molecular function are those primarily involved in synaptic function, notably "synaptic signaling, transmission and processing, " and "synaptic vesicle metabolism" (Wu et al, 2019). As for cellular component, relevant GO categories were those related to "synapse part, " "neuron part, " "synapse, " "pre-synapse, " "exocytic vesicle, " "transport vesicle, " "cytoplasmic, membranebounded vesicle, " "synaptic vesicle, " "secretory vesicle, " "neuron projection, " "exocytic vesicle membrane, " "synaptic vesicle membrane, " "post-synapse, " "transport vesicle membrane, " "cell junction, " "cytoplasmic vesicle part, " and "excitatory synapse."…”

“…As for cellular component, relevant GO categories were those related to "synapse part, " "neuron part, " "synapse, " "pre-synapse, " "exocytic vesicle, " "transport vesicle, " "cytoplasmic, membranebounded vesicle, " "synaptic vesicle, " "secretory vesicle, " "neuron projection, " "exocytic vesicle membrane, " "synaptic vesicle membrane, " "post-synapse, " "transport vesicle membrane, " "cell junction, " "cytoplasmic vesicle part, " and "excitatory synapse." For biological process, relevant GO categories were implicated in "synaptic signaling, " "anterograde trans-synaptic signaling, " "trans-synaptic signaling, " "chemical synaptic transmission, " and "cell-cell signaling" (Wu et al, 2019).…”

Single cell analysis of the effects of developmental lead (Pb) exposure on the hippocampus

“…One of our top downregulated genes overall, and within individual clusters, was Hbb-bs. A genetic mouse model for Alzheimer's disease, the Tg2576 mouse has lower levels of Hbb-bs in their hippocampus relative to wild type mice (Wu et al 2019), suggesting that this gene may play a role in Alzheimer's pathology in the hippocampus. We also identified significant downregulation of Kif5a, a kinesin gene involved in organelle transport.…”

Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease

“…NEK6 phosphorylates p70-S6 56 , a key player in hyperphosphorylation of Tau 57,58 that leads to microtubule disruption and deposition of Tau tangles. It was found to be relevant to the progression of AD and proposed as an early diagnostic biomarker 59,60 NEK9 was found to be differentially expressed in a tauopathy mouse model 61 .…”