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000273910 037__ $$aDZNE-2024-01384
000273910 041__ $$aEnglish
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000273910 1001_ $$aChoe, Kyonghwan$$b0
000273910 245__ $$aAlzheimer's disease-specific transcriptomic and epigenomic changes in the tryptophan catabolic pathway.
000273910 260__ $$aLondon$$bBioMed Central$$c2024
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000273910 520__ $$aNeurodegenerative 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.
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000273910 650_7 $$2Other$$aAlzheimer’s disease (AD)
000273910 650_7 $$2Other$$aBlood
000273910 650_7 $$2Other$$aBrain
000273910 650_7 $$2Other$$aEpigenetics
000273910 650_7 $$2Other$$aIndoleamine 2,3-dioxygenase (IDO)
000273910 650_7 $$2Other$$aTryptophan (TRP)
000273910 650_7 $$08DUH1N11BX$$2NLM Chemicals$$aTryptophan
000273910 650_7 $$00U46U6E8UK$$2NLM Chemicals$$aNAD
000273910 650_2 $$2MeSH$$aHumans
000273910 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000273910 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000273910 650_2 $$2MeSH$$aTryptophan: metabolism
000273910 650_2 $$2MeSH$$aMale
000273910 650_2 $$2MeSH$$aFemale
000273910 650_2 $$2MeSH$$aAged
000273910 650_2 $$2MeSH$$aAged, 80 and over
000273910 650_2 $$2MeSH$$aTranscriptome
000273910 650_2 $$2MeSH$$aDNA Methylation: genetics
000273910 650_2 $$2MeSH$$aEpigenomics: methods
000273910 650_2 $$2MeSH$$aCohort Studies
000273910 650_2 $$2MeSH$$aEpigenesis, Genetic: genetics
000273910 650_2 $$2MeSH$$aNAD: metabolism
000273910 650_2 $$2MeSH$$aTemporal Lobe: metabolism
000273910 650_2 $$2MeSH$$aMetabolic Networks and Pathways: genetics
000273910 7001_ $$aAli, Muhammad$$b1
000273910 7001_ $$aLardenoije, Roy$$b2
000273910 7001_ $$aRiemens, Renzo J M$$b3
000273910 7001_ $$aPishva, Ehsan$$b4
000273910 7001_ $$aBickel, Horst$$b5
000273910 7001_ $$aWeyerer, Siegfried$$b6
000273910 7001_ $$aHoffmann, Per$$b7
000273910 7001_ $$aPentzek, Michael$$b8
000273910 7001_ $$aRiedel-Heller, Steffi$$b9
000273910 7001_ $$aWiese, Birgitt$$b10
000273910 7001_ $$aScherer, Martin$$b11
000273910 7001_ $$0P:(DE-2719)2000057$$aWagner, Michael$$b12$$udzne
000273910 7001_ $$aMastroeni, Diego$$b13
000273910 7001_ $$aColeman, Paul D$$b14
000273910 7001_ $$0P:(DE-2719)2812825$$aRamirez, Alfredo$$b15$$udzne
000273910 7001_ $$aRamakers, Inez H G B$$b16
000273910 7001_ $$aVerhey, Frans R J$$b17
000273910 7001_ $$aRutten, Bart P F$$b18
000273910 7001_ $$aKenis, Gunter$$b19
000273910 7001_ $$avan den Hove, Daniel L A$$b20
000273910 773__ $$0PERI:(DE-600)2506521-X$$a10.1186/s13195-024-01623-4$$gVol. 16, no. 1, p. 259$$n1$$p259$$tAlzheimer's research & therapy$$v16$$x1758-9193$$y2024
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