Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach

Caterina Giovagnoni*, Muhammad Ali, Lars M.T. Eijssen, Richard Maes, Kyonghwan Choe, Monique Mulder, Jos Kleinjans, Antonio del Sol, Enrico Glaab, Diego Mastroeni, Elaine Delvaux, Paul Coleman, Mario Losen, Ehsan Pishva, Pilar Martinez-Martinez, Daniel L.A. van den Hove

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions. The SL pathway has been shown to be affected in several brain-related disorders, including Alzheimer's disease (AD). Recent evidence suggests that epigenetic dysregulation plays an important role in the pathogenesis of AD as well. Here, we use an integrative approach to better understand the relationship between epigenetic and transcriptomic processes in regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of 252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32 healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD patients. Additionally, methylomic analysis of the same subjects revealed parallel hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD. Subsequent gene regulatory network-based analysis identified 3 candidate genes, that is, SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression program from a diseased towards a healthy state. Together, this epigenomic and transcriptomic approach highlights the importance of SL-related genes in AD, and may provide novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways in AD.

Original languageEnglish
Pages (from-to)178-187
Number of pages10
JournalNeurobiology of Aging
Volume102
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Acknowledgments:
Funds have been provided by the Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Netherlands (Award #11532; Funded by the Dorpmans-Wigmans Foundation) (DvdH), the Baeter Laeve foundation, ZonMw Memorabel program (projectnr: 733050105), the International Foundation for Alzheimer Research (ISAO) (projectnr: 14545), Hersenstichting (projectnr: DR-2018-00274), the Interreg Europe EURLipids program (projectnr: 23) and by the Joint Programme—Neurodegenerative Disease Research (JPND) for the EPI-AD consortium. (http://www.neurodegenerationresearch.eu/wpcontent/uploads/2015/10/Factsheet_EPI-AD.pdf). The project is supported through the following funding organizations under the aegis of JPND; The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw); United Kingdom, Medical Research Council; Germany, German Federal ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 643417. Additional funds have been provided by a fellowship as part of NWO grant 022.005.019 and the GW4 Biomed MRC Doctoral Training Partnership. This research was further made possible by BReIN (Brightlands e-infrastructure for Neurohealth), an initiative which is co-funded by the Province of Limburg, Maastricht University and Maastricht University Medical Centre + in the Netherlands. This publication was also funded in part by the German Federal Ministry of Education and Research (BMBF) (grants Nr: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project “Diet-Body-Brain: from epidemiology to evidence-based communication”. EG acknowledges support by the Fondation Wivine Luxembourg. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human biological materials (or specific description, e.g., brain tissue, cerebrospinal fluid). The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research.

Publisher Copyright: © 2021

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