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CSF microRNA Profiling in Alzheimer’s Disease: a Screening and Validation Study

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Abstract

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression through post-transcriptional repression of target genes. They have been shown to be implicated in the pathophysiology of Alzheimer’s disease (AD) and proposed as disease biomarkers. In the present work, we have studied the expression levels of 754 miRNAs in cerebrospinal fluid (CSF) from AD patients and control subjects. We have explored a first screening cohort (N = 20) and selected 12 miRNAs to be further tested in a second independent validation cohort (N = 69). We have found a significant upregulation of miR-222 and miR-125b in AD CSF. Of these, the association of miR-222 with AD is novel and reported here for the first time whereas upregulation of miR-125b has been previously reported in AD brain. Yet we do not find association with other miRNAs which were previously linked to AD. Our results shed light on potential underlying pathophysiological processes of AD and also point out the need for consensus procedures in CSF miRNA detection and data analysis.

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Acknowledgments

This publication is part of the AETIONOMY project (Organising Mechanistic Knowledge about Neurodegenerative Diseases for the Improvement of Drug Development and Therapy) of the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AETIONOMY grant n° 115568. This study was also supported by the project PI11/03023, integrated in the National R + D + I Plan and co-financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa”), by grants to JLM (Consolider CSD2010-00045) and to A. Lladó (PI14/00282, ISCIII, Cofinancia FEDER, Unión Europea, “Otra manera de hacer Europa”) from the Spanish Ministry of Economy and Competitiveness, and by grants to A. Lleó (PI11/03035-BIOMARKAPD, PI14/01561, and “Marató TV3” grant 20142610) and to JF (PI11/02425, PI14/01126, and “Marató TV3” grant 20141210), jointly funded by Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa”). LR is the recipient of a Miguel Servet grant as a senior investigator (CP2/00023).

We are grateful to Dr. Lourdes Mengual for the helpful discussion in miRNA detection and to Dr. M.O. Boldi from Research Center for Statistics (Geneva, Switzerland) for the help with the statistics.

This work was developed at the Centre de Recerca Biomèdica Cellex in Barcelona, Spain.

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Authors and Affiliations

  1. Alzheimer’s disease and other cognitive disorders unit, Neurology Service, Hospital Clínic i Universitari-, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Villarroel 170, Barcelona, 08036, Spain

    Adrià Dangla-Valls, José Luis Molinuevo, Raquel Sánchez-Valle, Lorena Rami, Mircea Balasa, Cristina Muñoz-García, Albert Lladó & Anna Antonell

  2. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain

    José Luis Molinuevo

  3. Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Jordi Altirriba

  4. Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau—Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    Daniel Alcolea, Juan Fortea & Alberto Lleó

  5. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Daniel Alcolea, Juan Fortea & Alberto Lleó

  6. Laboratory of Neurodegenerative Disorders, Neurology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Mario Ezquerra & Rubén Fernández-Santiago

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  1. Adrià Dangla-Valls
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  2. José Luis Molinuevo
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Correspondence to José Luis Molinuevo.

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Expression levels in CSF in the validation phase of detectable (amplification in ≥50 % of the samples) but not significantly dysregulated miRNAs. Individual values of control subjects (CTR) are represented with circles, Alzheimer’s disease patients (AD) with squares, and horizontal lines show mean ± SD. (GIF 19 kb)

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Dangla-Valls, A., Molinuevo, J.L., Altirriba, J. et al. CSF microRNA Profiling in Alzheimer’s Disease: a Screening and Validation Study. Mol Neurobiol 54, 6647–6654 (2017). https://doi.org/10.1007/s12035-016-0106-x

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