title: microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer's disease triple transgenic mice.
abstract: The abnormal regulation of amyloid-β (Aβ) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Aβ production and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Aβ metabolism, including Tau, Mapk, and Sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target Sirt1, can directly regulate Aβ production in cells. Finally, both miR-132 and Sirt1 levels correlated with Aβ load in humans. Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aβ metabolism and senile plaque deposition in AD. This study strengthens the importance of miR-dependent networks in neurodegenerative disorders, and opens the door to multifactorial drug targets of AD by targeting Aβ and Tau.
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Hernandez-Rapp
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Rainone
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Goupil
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dorval
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Pascal Y
authors.initials: PY
authors.lastname: Smith
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Saint-Pierre
authors.affiliation: Axe Endocrinologie et néphrologie, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vallée
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.affiliation: Axe Endocrinologie et néphrologie, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de médecine moléculaire, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Droit
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Faculté de pharmacie, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
authors.affiliation: Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.|Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C546976:MIRN132 microRNA, mouse; C554518:MIRN212 microRNA, mouse; D035683:MicroRNAs; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1