MiRNA-15b and miRNA-125b are associated with regional A\u03b2-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

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

doi:10.1038/s41398-020-01184-8

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 18F-fluorodeoxyglucose-PET (18F-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 18F-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 18F-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.

Highlights

MicroRNAs—a class of endogenous, singlestranded, 22-ribonucleotide-average-sized, non-coding RNAs—modulate post-transcriptional gene expression by either repressing translation or degrading their target messenger RNAs after binding to the mRNAs 3′-untranslated region[1,2]
Study participants and cognitive assessment Sixty individuals with subjective memory complaint (SMC) were recruited from the standardized, large-scale, observational, monocentric, French academic university-based “INveStIGation of AlzHeimer’s PredicTors in Subjective Memory Complainers” (INSIGHT-preAD) study[35], that is part of the Alzheimer Precision Medicine Initiative (APMI) and its established Cohort Program (APMI-CP)[36]
We observed no significant association between age, sex, Apolipoprotein E ε4 (APOE ε4) status, and individual miRNA abundance or speciation, suggesting that miRNAs may represent an independent variable in specific neurological disease states

Summary

Introduction

MicroRNAs (miRNAs)—a class of endogenous, singlestranded, 22-ribonucleotide-average-sized, non-coding RNAs—modulate post-transcriptional gene expression by either repressing translation or degrading their target messenger RNAs (mRNAs) after binding to the mRNAs 3′-untranslated region[1,2]. In the brain and central nervous system (CNS) miRNAs appear to act as single-discrete. MiRNA expression patterns are complex and dynamic; for instance, the natural miRNA abundance is subject to alterations during neural development and differentiation of the human brain and in the CNS during aging[6,7,8]. Experimental models of aging and Alzheimer’s disease (AD), as well as in-human post-mortem and in vivo biomarker-based studies, indicate that the dysregulation of several miRNAs may influence AD pathophysiological mechanisms, including the amyloid-β (Aβ) pathway, tau pathology, brain immune, and inflammatory response, oxidative stress regulation, among others[7,8,9,10,11,12,13,14,15,16].

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Conclusion