Abstract
Sporadic early-onset Alzheimer’s disease (EOAD) and autosomal dominant Alzheimer’s disease (ADAD) provide the opportunity to investigate the physiopathological mechanisms in the absence of aging, present in late-onset forms. Frontotemporal dementia (FTD) causes early-onset dementia associated to tau or TDP43 protein deposits. A 15% of FTD cases are caused by mutations in C9orf72, GRN, or MAPT genes. Lymphoblastoid cell lines (LCLs) have been proposed as an alternative to brain tissue for studying earlier phases of neurodegenerative diseases. The aim of this study is to investigate the expression profile in EOAD, ADAD, and sporadic and genetic FTD (sFTD and gFTD, respectively), using brain tissue and LCLs. Sixty subjects of the following groups were included: EOAD, ADAD, sFTD, gFTD, and controls. Gene expression was analyzed with Clariom D microarray (Affymetrix). Brain tissue pairwise comparisons revealed six common differentially expressed genes (DEG) for all the patients’ groups compared with controls: RGS20, WIF1, HSPB1, EMP3, S100A11 and GFAP. Common up-regulated biological pathways were identified both in brain and LCLs (including inflammation and glial cell differentiation), while down-regulated pathways were detected mainly in brain tissue (including synaptic signaling, metabolism and mitochondrial dysfunction). CD163, ADAMTS9 and LIN7A gene expression disruption was validated by qPCR in brain tissue and NrCAM in LCLs in their respective group comparisons. In conclusion, our study highlights neuroinflammation, metabolism and synaptic signaling disturbances as common altered pathways in different AD and FTD forms. The use of LCLs might be appropriate for studying early immune system and inflammation, and some neural features in neurodegenerative dementias.
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Data Availability
The datasets generated during the current study are available in the NCBI’s GEO database under the accession number GSE195872.
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Acknowledgements
The authors thank patients and their relatives for their participation in research.
Funding
This work was supported by Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa” (PI17/00670 to Dr Antonell, PI20/00448 to Dr Sánchez-Valle and PFIS grant (FI18/00121) to O. Ramos-Campoy); Departament de Salut de la Generalitat de Catalunya (PERIS 2016-2020, SLT002/16/00329 and PERIS 2019-2021, SLT008/18/00061).
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A. Antonell and R. Sánchez-Valle contributed to the study conception and design, data analysis, and manuscript writing. Material preparation, data collection, and analysis were performed by O. Ramos-Campoy. M. Ferrer, R. Gonzalo, and A. Pérez-Millán contributed to data analysis. The first draft of the manuscript was written by O. Ramos-Campoy, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Ramos-Campoy, O., Lladó, A., Bosch, B. et al. Differential Gene Expression in Sporadic and Genetic Forms of Alzheimer’s Disease and Frontotemporal Dementia in Brain Tissue and Lymphoblastoid Cell Lines. Mol Neurobiol 59, 6411–6428 (2022). https://doi.org/10.1007/s12035-022-02969-2
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DOI: https://doi.org/10.1007/s12035-022-02969-2