INTEGRATIVE ANALYSIS OF CYTOKINE EXPRESSION VARIATION IN THE AGED HUMAN BRAIN

Juliana Beker Godoy; Ricardo A. Vialle; Shinya Tasaki; Yanling Wang; Vilas Menon; Philip L. De Jager; David A. Bennett; Dieval Guizelini; Katia de Paiva Lopes

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Paper Title

INTEGRATIVE ANALYSIS OF CYTOKINE EXPRESSION VARIATION IN THE AGED HUMAN BRAIN

Authors

Juliana Beker Godoy
Ricardo A. Vialle
Shinya Tasaki
Yanling Wang
Vilas Menon
Philip L. De Jager
David A. Bennett
Dieval Guizelini
Katia de Paiva Lopes

Modality

Poster

Subject area

RNA and transcriptomics

Publishing Date

21/11/2024

Country of Publishing

Brazil | Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeeting-2024/831857-integrative-analysis-of-cytokine-expression-variation-in-the-aged-human-brain

ISBN

978-65-272-0843-3

Keywords

single-nucleus RNASeq, cytokine, human brain, transcriptomics integration

Summary

Neurodegenerative diseases involve progressive neuron loss, with Alzheimer’s disease (AD) being the primary cause of dementia, accounting for 70% of cases. While its etiology remains uncertain, recent studies highlight the crucial role of neuroinflammation in AD pathogenesis. Cytokines, vital for maintaining homeostasis and coordinating immune responses in the brain, have emerged as notable contributors to AD progression. This study applies a framework integration to evaluate the correlation between cytokine expression and AD phenotype in aged brains. We examined RNA sequencing data from post-mortem human brain samples from two longitudinal clinical-pathologic cohorts: the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). We used bulk RNA-seq data from 1,210 individuals and single-nuclei profiles from a subset with 424 samples, covering seven brain cell type groups. Participants underwent annual clinical and cognitive assessments, ranging from controls to AD diagnosis. A total of 49 cytokines were expressed in the cortex. We filtered the gene expression matrices to use only the cytokines for the principal component analysis (PCA). Ten first principal components (PCs) were retained, capturing more than 62% and 70% of the cumulative variance in bulk and single-nuclei datasets, respectively. These PCs were used to calculate Spearman correlation with phenotypic measurements including cognitive decline, amyloid deposition, tangle density, global AD pathology burden, and age of death. We also ran the variancePartition (VP) R function to interpret drivers of cytokines expression. PC1, PC5, PC6, PC7, and PC10 from the bulk dataset were associated with at least one phenotype variable. PC1 accounts for the majority of bulk variance (19.19%), driven by growth factors (CSF1, FGF2, HGF), chemokines (CXCL8, CCL2), and genes as SPP1, C3, and TGFB1. This component was positively correlated with amyloid deposition (rs = 0.13336; p-value = 6.44x10-3) and AD diagnosis (rs = 0.1279; p-value = 0.008). At the cell type level, excitatory neurons showed the highest number of phenotype-associated PCs recapitulating the bulk associations, while other cell types showed some distinct effects. Specifically, microglia PC3 strongly correlated with AD diagnosis, tau and amyloid deposition, while microglia PC5 showed a strong inverse association with these variables. Oligodendrocyte PC2 (9.85% variance explained) was exclusively linked with neurofibrillary tangles (rs = 0.11132; p-value = 0.0231). Furthermore, we noticed that the AD-associated genetic risk factor APOE e4 had a minor impact on pro-inflammatory cytokine expression, explaining about 2% of SPP1 in oligodendrocytes, 1% of IL1B in microglia, 1% of IL17D in inhibitory neurons, and 1% of TNFSF12 in excitatory neurons. In conclusion, the methods used here allowed us to integrate distinct expression matrices and chase the variables that potentially affect the expression of cytokines in the brain. These findings highlight distinct neuroinflammation patterns across different brain cell types and the impact of phenotype on cytokine expression, providing insights for targeted therapeutic strategies in AD.

Title of the Event: 20º Congresso Brasileiro de Bioinformática: X-Meeting 2024
City of the Event: Salvador
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

GODOY, Juliana Beker et al.. INTEGRATIVE ANALYSIS OF CYTOKINE EXPRESSION VARIATION IN THE AGED HUMAN BRAIN.. In: X-Meeting presentations. Anais...Salvador(BA) Hotel Deville Prime, 2024. Available in: https//www.even3.com.br/anais/xmeeting-2024/831857-INTEGRATIVE-ANALYSIS-OF-CYTOKINE-EXPRESSION-VARIATION-IN-THE-AGED-HUMAN-BRAIN. Access in: 30/06/2025