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MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

2021; Springer Nature; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41398-020-01184-8

2158-3188

Andrea Vergallo, Simone Lista, Yuhai Zhao, Pablo Lemercier, Stefan Teipel, Marie‐Claude Potier, Marie‐Odile Habert, Bruno Dubois, Walter J. Lukiw, Harald Hampel, Hovagim Bakardjian, Habib Benali, Hugo Bertin, Joel Bonheur, Laurie Boukadida, Nadia Boukerrou, Enrica Cavedo, Patrizia Chiesa, Olivier Colliot, Bruno Dubois, Marion Dubois, Stéphane Epelbaum, Geoffroy Gagliardi, Remy Genthon, Marie-Odile Habert, Harald Hampel, Marion Houot, Aurélie Kas, Foudil Lamari, Marcel Lévy, Simone Lista, Christiane Metzinger, Fanny Mochel, Francis Nyasse, Catherine Poisson, Marie‐Claude Potier, Marie Revillon, Antonio Santos, Katia Santos Andrade, Marine Sole, Mohmed Surtee, Michel Thiebaut de Schotten, Andrea Vergallo, Nadjia Younsi, Bruno Dubois, Mohammad Afshar, Lisi Flores Aguilar, Leyla Akman-Anderson, Joaquín Arenas, Jesús Ávila, Claudio Babiloni, Filippo Baldacci, Richard Batrla, Norbert Benda, Keith L. Black, Arun L.W. Bokde, Ubaldo Bonuccelli, Karl Broich, Francesco Cacciola, Filippo Caraci, Giuseppe Caruso, Juan Carlos Martínez‐Castrillo, Enrica Cavedo, Roberto Ceravolo, Patrizia A. Chiesa, Massimo Corbo, Jean‐Christophe Corvol, A. Claudio Cuello, Jeffrey L. Cummings, Herman Depypere, Andrea Duggento, Enzo Emanuele, Valentina Escott-Price, Howard Federoff, Maria Teresa Ferretti, Massimo Fiandaca, Richard Frank, Francesco Garaci, Hugo Geerts, Ezio Giacobini, Filippo Sean Giorgi, Edward J. Goetzl, Manuela Graziani, Marion Haberkamp, Britta Hänisch, Karl Herholz, Félix Hernández, Bruno P. Imbimbo, Dimitrios Kapogiannis, Eric Karran, Steven J. Kiddle, Seung Hyun Kim, Yosef Koronyo, Maya Koronyo‐Hamaoui, Todd Langevin, Stéphane Lehéricy, Francisco Llavero, Jean Lorenceau, Alejandro Lucía, Dalila Mango, Mark Mapstone, Christian Néri, Robert Nisticò, Sid E. O’Bryant, Giovanni Palermo, George Perry, Karen Ritchie, Símone Rossi, Amira Saidi, Emiliano Santarnecchi, Lon S. Schneider, Olaf Sporns, Nicola Toschi, Pedro L. Valenzuela, Bruno Vellas, Steven Verdooner, Nicolas Villain, Kelly Virecoulon Giudici, Mark Watling, Lindsay A. Welikovitch, Janet Woodcock, Erfan Younesi, José L. Zugaza,

Extracellular vesicles in disease

Abstract There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 ( APOE ε4 ) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18 F-fluorodeoxyglucose-PET ( 18 F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18 F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18 F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.