Research Paper Volume 15, Issue 22 pp 13077—13099
Identification of tryptophan metabolism-related genes in immunity and immunotherapy in Alzheimer’s disease
- 1 School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- 2 Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
Received: June 28, 2023 Accepted: October 15, 2023 Published: November 20, 2023
https://doi.org/10.18632/aging.205220How to Cite
Copyright: © 2023 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Recent studies have highlighted the significant involvement of tryptophan metabolism in the pathogenesis of Alzheimer’s disease (AD). However, a comprehensive investigation of the precise role of tryptophan metabolism in the context of AD is still lacking. This study employed a bioinformatics approach to identify and validate potential tryptophan metabolism-related genes (TrpMgs) associated with AD. The discovery of TrpMgs was facilitated through the intersection of the Weighted Gene Co-expression Network Analysis (WGCNA) test and 17 known tryptophan metabolism pathways. Subsequently, the putative biological functions and pathways of the TrpMgs were elucidated using Gene Set Variation Analysis (GSVA). Furthermore, the Least Absolute Shrinkage and Selection Operator (LASSO) method was applied to identify hub genes and evaluate the diagnostic efficiency of the 5 TrpMgs in distinguishing AD. The relationship between hub TrpMgs and clinical characteristics was also investigated. Finally, in vivo verification of the five TrpMgs was performed using APP/PS1 mice. We identified 5 TrpMgs associated with AD, including propionyl-CoA carboxylase subunit beta (PCCB), TEA Domain Transcription Factor 1 (TEAD1), Phenylalanyl-TRNA Synthetase Subunit Beta (FARSB), Neurofascin (NFASC), and Ezrin (EZR). Among these genes, PCCB, FARSB, NFASC, and TEAD1 showed correlations with age. In the hippocampus of APP/PS1 mice, we observed down-regulation of FARSB, PCCB, and NFASC mRNA expressions. Furthermore, PCCB and NFASC protein expressions were also down-regulated in the cerebral cortex and hippocampus of APP/PS1 mice. Our study paves the way for future research aimed at unraveling the intricate mechanisms underlying tryptophan metabolism dysregulation in AD and its therapeutic implications.
Abbreviations
3-HK: 3-hydroxykynurenine; AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; AUC: Area under the curve; Aβ: Amyloid β; BP: Biological processes; CC: Cellular components; CSF: Cerebrospinal fluid; DEGs: Differentially Expressed Genes; EZR: Ezrin; FARSB: Phenylalanyl-tRNA Synthetase Subunit Beta; GEO: Gene Expression Omnibus; GO: Gene Ontology; GSVA: Gene Set Variation Analysis; IDO: Indoleamine 2,3-dioxygenase; KATs: Kynurenine aminotransferases; KEGG: Kyoto Encyclopedia of Genes and Genomes; KMO: Kynurenine monooxygenase; KYN: Kynurenine; KYNA: Kynurenic acid; LASSO: Least Absolute Shrinkage and Selection Operator; MF: Molecular functions; NFASC: Neurofascin; NMDA: N-methyl-D-aspartic acid; PCCB: Propionyl-CoA carboxylase subunit beta; TCM: Traditional Chinese medicine; TDO: Tryptophan 2,3-dioxygenase; TEAD1: TEA Domain Transcription Factor; Tregs: Regulatory T cells; Trp: Tryptophan; TrpMgs: Tryptophan metabolism-related genes; TXNIP: Thioredoxin-interacting protein; WGCNA: Weighted Gene Co-expression Network Analysis; α7nACh: α7 nicotinic acetylcholine.