TY - JOUR
T1 - MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints
AU - for the INSIGHT-preAD study group
AU - the Alzheimer Precision Medicine Initiative (APMI)
AU - Vergallo, Andrea
AU - Lista, Simone
AU - Zhao, Yuhai
AU - Lemercier, Pablo
AU - Teipel, Stefan J.
AU - Potier, Marie Claude
AU - Habert, Marie Odile
AU - Dubois, Bruno
AU - Lukiw, Walter J.
AU - Hampel, Harald
AU - Bakardjian, Hovagim
AU - Benali, Habib
AU - Bertin, Hugo
AU - Bonheur, Joel
AU - Boukadida, Laurie
AU - Boukerrou, Nadia
AU - Cavedo, Enrica
AU - Chiesa, Patrizia
AU - Colliot, Olivier
AU - Dubois, Bruno
AU - Dubois, Marion
AU - Epelbaum, Stéphane
AU - Gagliardi, Geoffroy
AU - Genthon, Remy
AU - Habert, Marie Odile
AU - Houot, Marion
AU - Kas, Aurélie
AU - Lamari, Foudil
AU - Levy, Marcel
AU - Lista, Simone
AU - Metzinger, Christiane
AU - Mochel, Fanny
AU - Nyasse, Francis
AU - Poisson, Catherine
AU - Potier, Marie Claude
AU - Revillon, Marie
AU - Santos, Antonio
AU - Andrade, Katia Santos
AU - Sole, Marine
AU - Surtee, Mohmed
AU - de Schotten, Michel Thiebaut
AU - Vergallo, Andrea
AU - Younsi, Nadjia
AU - Dubois, Bruno
AU - Afshar, Mohammad
AU - Aguilar, Lisi Flores
AU - Akman-Anderson, Leyla
AU - Arenas, Joaquín
AU - Ávila, Jesús
AU - O’Bryant, Sid E.
N1 - Funding Information:
The research and this manuscript was part of the translational research program “PHOENIX”, awarded to H.H., and administered by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received support within the “Investissement d’Avenir” (ANR-10-AIHU-06) French program. The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. CATI is a French neuroimaging platform funded by the French Plan Alzheimer (available at http://cati-neuroimaging.com). A.V. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. H.H. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. At Sorbonne University he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer”, Paris, France. W.J.L.: research on miRNA in the Lukiw laboratory involving the innate-immune response in AD and in other forms of neurological or retinal disease, amyloidogenesis, and neuro-inflammation was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100101325&partnerID=8YFLogxK
U2 - 10.1038/s41398-020-01184-8
DO - 10.1038/s41398-020-01184-8
M3 - Article
C2 - 33504764
AN - SCOPUS:85100101325
SN - 2158-3188
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 78
ER -