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@ARTICLE{Choe:273910,
      author       = {Choe, Kyonghwan and Ali, Muhammad and Lardenoije, Roy and
                      Riemens, Renzo J M and Pishva, Ehsan and Bickel, Horst and
                      Weyerer, Siegfried and Hoffmann, Per and Pentzek, Michael
                      and Riedel-Heller, Steffi and Wiese, Birgitt and Scherer,
                      Martin and Wagner, Michael and Mastroeni, Diego and Coleman,
                      Paul D and Ramirez, Alfredo and Ramakers, Inez H G B and
                      Verhey, Frans R J and Rutten, Bart P F and Kenis, Gunter and
                      van den Hove, Daniel L A},
      title        = {{A}lzheimer's disease-specific transcriptomic and
                      epigenomic changes in the tryptophan catabolic pathway.},
      journal      = {Alzheimer's research $\&$ therapy},
      volume       = {16},
      number       = {1},
      issn         = {1758-9193},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2024-01384},
      pages        = {259},
      year         = {2024},
      abstract     = {Neurodegenerative disorders, including Alzheimer's disease
                      (AD), have been linked to alterations in tryptophan (TRP)
                      metabolism. However, no studies to date have systematically
                      explored changes in the TRP pathway at both transcriptional
                      and epigenetic levels. This study aimed to investigate
                      transcriptomic, DNA methylomic (5mC) and hydroxymethylomic
                      (5hmC) changes within genes involved in the TRP and
                      nicotinamide adenine dinucleotide (NAD) pathways in AD,
                      using three independent cohorts.DNA derived from post-mortem
                      middle temporal gyrus (MTG) tissue from AD patients (n = 45)
                      and age-matched controls (n = 35) was analyzed, along with
                      DNA derived from blood samples from two independent cohorts:
                      the German Study on Ageing, Cognition, and Dementia in
                      Primary Care Patients (AgeCoDe) cohort (n = 96) and the
                      Dutch BioBank Alzheimer Center Limburg (BBACL) cohort (n =
                      262). Molecular profiling, including assessing mRNA
                      expression and DNA (hydroxy)methylation levels, was
                      conducted using HumanHT-12 v4 Expression BeadChip and HM 450
                      K BeadChip arrays, respectively. Functional interactions
                      between genes and identification of common
                      phenotype-specific positive and negative elementary circuits
                      were conducted using computational modeling, i.e. gene
                      regulatory network (GRN) and network perturbational
                      analysis. DNA methylation of IDO2 (cg11251498) was analyzed
                      using pyrosequencing.Twelve TRP- and twenty NAD-associated
                      genes were found to be differentially expressed in the MTG
                      of AD patients. Gene sets associated in the kynurenine
                      pathway, the most common TRP pathway, and NAD pathway,
                      showed enrichment at the mRNA expression level. Downstream
                      analyses integrating data on gene expression, DNA
                      (hydroxy)methylation, and AD pathology, as well as GRN and
                      network perturbation analyses, identified IDO2, an immune
                      regulatory gene, as a key candidate in AD. Notably, one CpG
                      site in IDO2 (cg11251498) exhibited significant methylation
                      differences between AD converters and non-converters in the
                      AgeCoDe cohort.These findings reveal substantial
                      transcriptional and epigenetic alterations in TRP- and
                      NAD-pathway-associated genes in AD, highlighting IDO2 as a
                      key candidate gene for further investigation. These genes
                      and their encoded proteins hold potential as novel
                      biomarkers and therapeutic targets for AD.},
      keywords     = {Humans / Alzheimer Disease: genetics / Alzheimer Disease:
                      metabolism / Tryptophan: metabolism / Male / Female / Aged /
                      Aged, 80 and over / Transcriptome / DNA Methylation:
                      genetics / Epigenomics: methods / Cohort Studies /
                      Epigenesis, Genetic: genetics / NAD: metabolism / Temporal
                      Lobe: metabolism / Metabolic Networks and Pathways: genetics
                      / Alzheimer’s disease (AD) (Other) / Blood (Other) / Brain
                      (Other) / Epigenetics (Other) / Indoleamine 2,3-dioxygenase
                      (IDO) (Other) / Tryptophan (TRP) (Other) / Tryptophan (NLM
                      Chemicals) / NAD (NLM Chemicals)},
      cin          = {AG Wagner / Patient Studies (Bonn)},
      ddc          = {610},
      cid          = {I:(DE-2719)1011201 / I:(DE-2719)1011101},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39616392},
      pmc          = {pmc:PMC11607912},
      doi          = {10.1186/s13195-024-01623-4},
      url          = {https://pub.dzne.de/record/273910},
}