Alzheimer's disease (AD) is a chronic, progressive brain disorder that slowly destroys affected individuals’ memory and reasoning faculties, and consequently, their ability to perform the simplest tasks. This study investigated the hub genes of AD. Proteins interact with other proteins and non-protein molecules, and these interactions play an important role in understanding protein function. Computational methods are useful for understanding biological problems, in particular, network analyses of protein-protein interactions. Through a protein network analysis, we identified the following top 10 hub genes associated with AD:
As people become older, many parts of the body, including the brain, change. It is also normal for people to become forgetful, and age-associated memory impairment is considered to be part of the aging process. However, Alzheimer's disease (AD) is distinct from age-associated memory impairment, and instead is a type of dementia that causes problems with memory, thinking, and behavior. Hence, it is understandable that people, especially the elderly, are concerned about memory loss, as it is a symptom of AD. Dementia is known to be progressive, meaning that the condition becomes worse gradually. It is well known that AD has complicated and diverse pathogenic causes, including genetic, environmental, and immunological factors, as well as head trauma, depression, and hypertension. Moreover, genetic analyses have shown that human variations in AD can originate from several genes and their variants, which exert different biological functions in coordination to increase disease risk. AD typically occurs in elderly people (aged 65 years and above), while an uncommon variant known as early-onset AD comprises about 5% of AD cases [
According to the National Institute on Aging (
Previous research has determined that carriers of the
DisGeNET (
For this study, Cytoscape (
To determine the potential hub genes of AD, CytoHubba [
FunRich (
AlzData is an integrated AD database that uses high-throughput omics data such as the results of genome-wide association studies (GWAS), whole-exome sequencing, transcriptome analysis, and proteomics to generate a prioritized gene list. We used this database to prioritize the top 10 hub genes identified.
In the data downloaded from DisGeNET (accessed December 2019), there were 1981 genes involved in AD (
Regarding the molecular function of the AD hub genes (
In terms of biological processes (
PTGER3 and prostaglandin E2 are derived from the metabolism of arachidonic acid by cyclooxygenases in the cyclooxygenase pathway. This protein is the main neuroinflammatory molecule [
A widely expressed gene in the CNS,
The
The endocannabinoid system (ECS) comprises endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors. The ECS is involved in regulating physiological and cognitive processes, including include memory. One of the key receptors, cannabinoid receptor 2, is encoded by
We used the convergent functional genomics (CFG) ranking for target genes available in the AlzData database. AlzData (
Protein-protein interactions are important for understanding protein function and behavior. In this study, we identified 10 hub genes of AD. The results show that most of these genes encode receptor proteins that are involved in biological pathways in the plasma membrane. The hub genes identified through a network analysis can be used as targets to suppress AD in patients. Our analysis can shed some light on a deeper understanding of the fundamental molecular pathways and key molecular players of AD and offers a new point of view for researchers studying the causes of AD.
Conceptualization: SK. Formal analysis:JJW. Writing - original draft: JJW, SK. Writing - review & editing: SK.
No potential conflict of interest relevant to this article was reported.
Supplementary data can be found with this article online at
List of 1,981 genes associated with Alzheimer's disease retrieved from Disgenet database
Overview of the protein-protein interaction network created using the STRING 10.0 database and Cytoscape software. The network has 1922 nodes and 57,617 edges. The analysis parameters are based on experiments, co-expression, and text mining with a 0.40 confidence score. The red circular nodes represent the hub genes interacting with other Alzheimer's disease‒associated genes, which are shown as small green circular nodes.
Cellular components of Alzheimer's disease hub genes.
Molecular functions of Alzheimer's disease hub genes.
Biological processes of Alzheimer's disease hub genes.
Biological pathways of Alzheimer's disease hub genes.
CFG ranking of top the 10 hub genes of AD
Gene | eQTL | GWAS | PPI | Early_DEG | Pathology cor (Aβ) | Pathology cor (tau) | CFG |
---|---|---|---|---|---|---|---|
1 | 0 | APP, PSEN1, APOE | NA | NA | NA | 2 | |
0 | 0 | APP, APOE | NA | NA | NA | 1 | |
NA | 1 | APP | Yes | ‒0.374* | 0.166 ns | 4 | |
NA | 0 | APP | NA | ‒0.082 ns | ‒0.481 ns | 1 | |
1 | 0 | APP, PSEN1, MAPT, APOE | Yes | 0.432** | ‒0.069 ns | 4 | |
1 | 0 | APP | Yes | 0.769*** | 0.616* | 4 | |
1 | 0 | APP, PSEN1, APOE | NA | NA | NA | 2 | |
1 | 0 | APP, PSEN1, APOE | Yes | 0.854*** | 0.750** | 4 | |
1 | 0 | APP | NA | NA | NA | 2 | |
NA | 0 | NA | NA | NA | NA | 0 |
CFG, convergent functional genomics; AD, Alzheimer's disease; GWAS, genome-wide association studies; PPI, protein protein interaction; DEG, differentially expressed gene; Aβ, beta-amyloids; NA, not available.
eQTL: expression of target gene is regulated by AD genetic variants (genetic variants: IGAP GWAS P < 1E-3; eQTL: p < 1E-3); GWAS: IGAP p < 1E-3; PPI: target gene has significant physical interaction with APP, PSEN1, PSEN2, APOE, or MAPT (p < 0.05); Early_DEG: target gene is differentially expressed in AD mouse models before AD pathology emergence; Pathology cor (Aβ): correlation of target gene expression with AD pathology in Aβ-line AD mouse models (r, p; ns, p > 0.05; *p <0.05, **p < 0.01, ***p < 0.001); Pathology cor (tau): correlation of target gene expression with AD pathology in tau line AD mouse models (r, p; ns, p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001); CFG: total CFG score of a target gene, 1 CFG point is assigned if any of the above evidence is significant, the total of CFG points ranges from 0 to 5.