Cognitive dysfunction associated with various diseases and its biomarkers have been extensively studied. However, research focusing on biomarkers related to cognitive function remains limited. This study aims to identify potential biomarkers associated with cognitive function and validate them through in vitro and in vivo experiments to address the current research gaps. We employed GWAS, PWAS, and TWAS analyses, combined with Mendelian randomization and colocalization analysis, to identify potential cognitive function-related biomarkers from European cohorts. An Alzheimer's disease (AD) cell model was established in SH-SY5Y and BV2 cells using Aβ25–35 oligomers, and an APP/PS1 (AD mouse model) was purchased. The mRNA and protein expression levels of potential biomarkers were assessed in AD cells and mouse models using RT-qPCR and western blotting. Immunofluorescence was used to evaluate the fluorescence expression of these biomarkers in the AD cells, while immunohistochemistry was employed to assess staining intensity in the dorsolateral prefrontal cortex of AD model mice. Three potential biomarkers associated with cognitive function were identified: GPX1, CSE1L, and SULT1A1. KEGG enrichment analysis indicated that GPX1, CSE1L, and SULT1A1 are involved in various metabolic pathways, including those related to amyotrophic lateral sclerosis and Huntington's disease signaling. RT-qPCR and western blotting revealed low expression of GPX1 and CSE1L, and high expression of SULT1A1 in both AD cells and mouse models. These findings were further confirmed by immunofluorescence and immunohistochemistry, which demonstrated similar expression patterns in the AD cell and mouse models. GPX1, CSE1L, and SULT1A1 serve as biomarkers of cognitive function.
KielyKM. Cognitive function. In: MagginoF (eds) Encyclopedia of quality of life and well-being research. Cham: Springer International Publishing, 2023, pp.1078–1081.
LongSBenoistCWeidnerW. World Alzheimer report 2023. Reducing dementia risk: never too early, never too late. London: Alzheimer’s Disease International, 2023.
Alzheimer's Disease International. World Alzheimer report 2024. Global changes in attitudes to dementia. London: Alzheimer’s Disease International, 2024.
AhmadAImranMAhsanH. Biomarkers as biomedical bioindicators: approaches and techniques for the detection, analysis, and validation of novel biomarkers of diseases. Pharmaceutics2023; 15: 1630.
19.
StrimbuKTavelJA. What are biomarkers?Curr Opin HIV AIDS2010; 5: 463–466.
20.
JiaJNingYChenM, et al.Biomarker changes during 20 years preceding Alzheimer's disease. N Engl J Med2024; 390: 712–722.
21.
BatemanRJXiongCBenzingerTL, et al.Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med2012; 367: 795–804.
22.
HorieKSalvadóGBarthélemyNR, et al.CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease. Nat Med2023; 29: 1954–1963.
23.
MuralidarSAmbiSVSekaranS, et al.Role of tau protein in Alzheimer's disease: the prime pathological player. Int J Biol Macromol2020; 163: 1599–1617.
24.
RawatPSeharUBishtJ, et al.Phosphorylated tau in Alzheimer's disease and other tauopathies. Int J Mol Sci2022; 23: 12841.
25.
WegmannSBiernatJMandelkowE. A current view on tau protein phosphorylation in Alzheimer's disease. Curr Opin Neurobiol2021; 69: 131–138.
26.
KatayamaTSawadaJTakahashiK, et al.Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimers Res Ther2021; 13: 163.
27.
PalmerJMHuentelmanMRyanL. More than just risk for Alzheimer’s disease: APOE ε4's impact on the aging brain. Trends Neurosci2023; 46: 750–763.
28.
Fernández-CalleRKoningsSCFrontiñán-RubioJ, et al.APOE In the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases. Mol Neurodegener2022; 17: 62.
29.
NgATamWWZhangMW, et al.IL-1β, IL-6, TNF-α and CRP in elderly patients with depression or Alzheimer's disease: systematic review and meta-analysis. Sci Rep2018; 8: 12050.
30.
KaurSBansalY. Design, molecular Docking, synthesis and evaluation of xanthoxylin hybrids as dual inhibitors of IL-6 and acetylcholinesterase for Alzheimer's disease. Bioorg Chem2022; 121: 105670.
31.
ShaoMChenKZhangS, et al.Multiome-wide association studies: novel approaches for understanding diseases. Genomics Proteomics Bioinformatics2024; 22: qzae077.
32.
HasinYSeldinMLusisA. Multi-omics approaches to disease. Genome Biol2017; 18: 83.
33.
UffelmannEHuangQQMunungNS, et al.Genome-wide association studies. Nat Rev Methods Primers2021; 1: 59.
34.
BrandesNLinialNLinialM. PWAS: proteome-wide association study—linking genes and phenotypes by functional variation in proteins. Genome Biol2020; 21: 173.
35.
LuMZhangYYangF, et al.TWAS Atlas: a curated knowledgebase of transcriptome-wide association studies. Nucleic Acids Res2023; 51: D1179–D1187.
36.
WainbergMSinnott-ArmstrongNMancusoN, et al.Opportunities and challenges for transcriptome-wide association studies. Nat Genet2019; 51: 592–599.
37.
MaiJLuMGaoQ, et al.Transcriptome-wide association studies: recent advances in methods, applications and available databases. Commun Biol2023; 6: 899.
38.
WingoAPLiuYGerasimovES, et al.Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis. Nat Genet2021; 53: 143–146.
39.
WangZZhangZLiP, et al.Multi-omics analysis reveals the genetic aging landscape of Parkinson’s disease. Sci Reps2024; 14: 31167.
40.
LeeJJWedowROkbayA, et al.Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat Genet2018; 50: 1112–1121.
41.
Fawns-RitchieCDearyIJ. Reliability and validity of the UK Biobank cognitive tests. PLoS One2020; 15: e0231627.
42.
BrandesNLinialNLinialM. PWAS: proteome-wide association study-linking genes and phenotypes by functional variation in proteins. Genome Biol2020; 21: 173.
43.
WingoTSLiuYGerasimovES, et al.Brain proteome-wide association study implicates novel proteins in depression pathogenesis. Nat Neurosci2021; 24: 810–817.
44.
BennettDABuchmanASBoylePA, et al.Religious orders study and rush memory and aging project. J Alzheimers Dis2018; 64: S161–S189.
45.
BeachTGAdlerCHSueLI, et al.Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology2015; 35: 354–389.
46.
VõsaUClaringbouldAWestraH-J, et al.Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet2021; 53: 1300–1310.
47.
GusevAKoAShiH, et al.Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet2016; 48: 245–252.
48.
SandersonESpillerWBowdenJ. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med2021; 40: 5434–5452.
49.
BurgessSThompsonSG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol2011; 40: 755–764.
50.
BirneyE. Mendelian randomization. Cold Spring Harb Perspect Med2022; 12: a041302.
51.
GiambartolomeiCVukcevicDSchadtEE, et al.Bayesian Test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet2014; 10: e1004383.
52.
BuDLuoHHuoP, et al.KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic Acids Res2021; 49: W317–W325.
53.
ShenWSongZZhongX, et al.Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform. Imeta2022; 1: e36.
54.
VandendriesscheCKapogiannisDVandenbrouckeRE. Biomarker and therapeutic potential of peripheral extracellular vesicles in Alzheimer's disease. Adv Drug Deliv Rev2022; 190: 114486.
55.
TherriaultJPascoalTALussierFZ, et al.Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging2022; 2: 526–535.
56.
LiLYuXShengC, et al.A review of brain imaging biomarker genomics in Alzheimer's disease: implementation and perspectives. Transl Neurodegener2022; 11: 42.
57.
SutherlandMShankaranarayananPScheweT, et al.Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism. Biochem J2001; 353: 91–100.
58.
SchwarzMLöserAChengQ, et al.Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides. Redox Biol2023; 59: 102593.
59.
MaYYuanXWeiA, et al.Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1. Redox Biol2024; 77: 103376.
60.
LiYLiuTZhengR, et al.Translational selenium nanoparticles boost GPx1 activation to reverse HAdV-14 virus-induced oxidative damage. Bioact Mater2024; 38: 276–291.
61.
LiYLiangJJiangC, et al.Se alleviated Pb-caused neurotoxicity in chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO pathway, selenoprotein suppression, oxidative stress, and inflammatory injury. Antioxidants (Basel)2024; 13: 370.
62.
WangSHLeeDSKimTH, et al.Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways. Cell Death Dis2024; 15: 707.
63.
da RochaTJSilva AlvesMGuissoCC, et al.Association of GPX1 and GPX4 polymorphisms with episodic memory and Alzheimer's disease. Neurosci Lett2018; 666: 32–37.
64.
SousaJACallejasBEWangA, et al.GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn's disease. Cell Death Dis2024; 15: 903.
65.
QuJWuLMouL, et al.Polystyrene microplastics trigger testosterone decline via GPX1. Sci Total Environ2024; 947: 174536.
66.
IqbalMWShahabMZhengG, et al.Analysis of damaging non-synonymous SNPs in GPx1 gene associated with the progression of diverse cancers through a comprehensive in silico approach. Sci Rep2024; 14: 28690.
67.
LeiFJChiangJYChangHJ, et al.Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma. Redox Biol2023; 65: 102831.
68.
LeeDHSonDJParkMH, et al.Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation. Cell Death Dis2016; 7: e2208.
69.
LiuRMaJZhangY, et al.Integrated transcriptome analysis of CSE1L regarding poor prognosis and immune infiltration in bladder urothelial carcinoma and experimental verification. Front Immunol2024; 15: 1449251.
70.
LiGLiRWangW, et al.DDX27 Regulates oral squamous cell carcinoma development through targeting CSE1L. Life Sci2024; 340: 122479.
71.
LiuXYWangYHWangJ, et al.The role of CSE1L silencing in the regulation of proliferation and apoptosis via the AMPK/mTOR signaling pathway in chronic myeloid leukemia. Hematology2023; 28: 1–9.
72.
LinHCLiJChengDD, et al.Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway. Mol Ther Oncolytics2021; 21: 23–36.
73.
YeMChenYLiuJ, et al.Interfering with CSE1L/CAS inhibits tumour growth via C3 in triple-negative breast cancer. Cell Prolif2022; 55: e13226.
74.
TunccanTKılıcCDuranAB, et al.Role of CSE1L expression in determining recurrence and survival of laryngeal tumors. Eur Arch Otorhinolaryngol2022; 279: 3639–3644.
75.
SalviAYoungANHuntsmanAC, et al.PHY34 Inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer. Cell Death Dis2022; 13: 45.
76.
ZhangXZhangXMaoT, et al.CSE1L, As a novel prognostic marker, promotes pancreatic cancer proliferation by regulating the AKT/mTOR signaling pathway. J Cancer2021; 12: 2797–2806.
77.
LiuCWeiJXuK, et al.CSE1L Participates in regulating cell mitosis in human seminoma. Cell Prolif2019; 52: e12549.
78.
LeeWRShenSCWuPR, et al.CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells. Mol Carcinog2016; 55: 1542–1552.
79.
LiHWangLRuanZ, et al.CSE1L As a prognostic biomarker associated with pan cancer immune infiltration and drug sensitivity. Expert Rev Clin Immunol2024; 20: 1113–1125.
80.
LeeWRShenSCShihYH, et al.Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts. J Transl Med2015; 13: 191.
81.
DuanLTadiMJMakiCG. CSE1L Is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor. Sci Rep2023; 13: 16271.
82.
Ravnik GlavačMMezzavillaMDolinarA, et al.Aberrantly expressed Hsa_circ_0060762 and CSE1L as potential peripheral blood biomarkers for ALS. Biomedicines2023; 11: 1316.
83.
KesterMHKapteinERoestTJ, et al.Characterization of human iodothyronine sulfotransferases. J Clin Endocrinol Metab1999; 84: 1357–1364.
84.
GamageNUDugglebyRGBarnettAC, et al.Structure of a human carcinogen-converting enzyme, SULT1A1. Structural and kinetic implications of substrate inhibition. J Biol Chem2003; 278: 7655–7662.
85.
ChouHCLangNPKadlubarFF. Metabolic activation of N-hydroxy arylamines and N-hydroxy heterocyclic amines by human sulfotransferase(s). Cancer Res1995; 55: 525–529.
86.
NeedhamBDFunabashiMAdameMD, et al.A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature2022; 602: 647–653.
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