[en] Background: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are complex neurodegenerative disorders with common pathological features, but the molecular mechanisms underlying their early stages remain poorly understood. This study aims to elucidate common and divergent changes in cellular processes in the early stages of neurodegeneration and neuroinflammation using brain organoid models.
Methods: We performed a multi-level comparative analysis of single-cell RNA sequencing data from brain organoid models previously designed to mimic specific features of PD- and AD-like pathology, integrating gene expression, pathway enrichment, molecular network, and cell–cell communication analyses. Given the critical role of neuroinflammation in neurodegenerative disorders, we particularly focused on inflammatory signaling pathways and alterations in cell–cell communication that might drive disease progression.
Results: Our findings reveal both common and contrasting changes between the different organoid models, including a common dysregulation of apoptotic pathways in astrocytes, a common upregulation of energy metabolism pathways in neurons, and opposing trends in ribosome-related pathways. Notably, our multi-level analysis identified key inflammatory alterations, including contrasting changes mediated by HMGB1 and shared dysregulation in the MDK signaling pathway. Finally, comparison with post-mortem brain tissue and GWAS data revealed a small set of overlapping significant genes, showing robust shared patterns across different stages of pathology and tissue sources.
Conclusions: These results provide new insights into the molecular basis of neurodegeneration and neuroinflammation, highlighting diverging and shared alterations between different organoid models and post-mortem brain tissues that may inform follow-up validation and preclinical intervention studies for neurodegenerative disorders.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group)
Disciplines :
Neurology Human health sciences: Multidisciplinary, general & others Biotechnology Life sciences: Multidisciplinary, general & others
Author, co-author :
Le Bars, S.
Soudy, M.
Nickels, S. L.
Schwamborn, J. C.
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
External co-authors :
no
Language :
English
Title :
Single-cell analysis reveals shared and distinct molecular signatures in brain organoid models of neurodegeneration and neuroinflammation
Publication date :
2025
Journal title :
Alzheimer's Research and Therapy
eISSN :
1758-9193
Publisher :
BioMed Central, London, United Kingdom
Volume :
in press
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Development Goals :
3. Good health and well-being
FnR Project :
FNR17999421 - AD-PLCG2 - Towards Druggable Targets In Alzheimer’S Disease Through Characterization Of Plcg2-related Pathways In Neurons And Microglia, 2023 (01/07/2024-30/06/2027) - Enrico Glaab
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