title: miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.
abstract: Alzheimer's disease (AD) and related tauopathies comprise a large group of neurodegenerative diseases associated with the pathological aggregation of tau protein. While much effort has focused on understanding the function of tau, little is known about the endogenous mechanisms regulating tau metabolism in vivo and how these contribute to disease. Previously, we have shown that the microRNA (miRNA) cluster miR-132/212 is downregulated in tauopathies such as AD. Here, we report that miR-132/212 deficiency in mice leads to increased tau expression, phosphorylation and aggregation. Using reporter assays and cell-based studies, we demonstrate that miR-132 directly targets tau mRNA to regulate its expression. We identified GSK-3β and PP2B as effectors of abnormal tau phosphorylation in vivo. Deletion of miR-132/212 induced tau aggregation in mice expressing endogenous or human mutant tau, an effect associated with autophagy dysfunction. Conversely, treatment of AD mice with miR-132 mimics restored in part memory function and tau metabolism. Finally, miR-132 and miR-212 levels correlated with insoluble tau and cognitive impairment in humans. These findings support a role for miR-132/212 in the regulation of tau pathology in mice and humans and provide new alternatives for therapeutic development.
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Pascal Y
authors.initials: PY
authors.lastname: Smith
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Julia
authors.initials: J
authors.lastname: Hernandez-Rapp
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Francis
authors.initials: F
authors.lastname: Jolivette
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Médecine Moléculaire.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lecours
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Médecine Moléculaire.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Bisht
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Claudia
authors.initials: C
authors.lastname: Goupil
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dorval
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Parsi
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Françoise
authors.initials: F
authors.lastname: Morin
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Faculté de Médecine, Université de Lille, UDSL, Lille F-59045, France and UMR-S 1172, Alzheimer and Tauopathies, Inserm, Lille F-59045, France.
authors.forename: Francisco-Jose
authors.initials: FJ
authors.lastname: Fernandez-Gomez
authors.affiliation: Faculté de Médecine, Université de Lille, UDSL, Lille F-59045, France and UMR-S 1172, Alzheimer and Tauopathies, Inserm, Lille F-59045, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Faculté de Médecine, Université de Lille, UDSL, Lille F-59045, France and UMR-S 1172, Alzheimer and Tauopathies, Inserm, Lille F-59045, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Médecine Moléculaire.
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Tremblay
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Faculté de Pharmacie, Université Laval, Québec, QC, Canada G1V 0A6.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2, Département de Psychiatrie et Neurosciences, sebastien.hebert@neurosciences.ulaval.ca.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D024801:Tauopathies / Q000378:metabolism* / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C547077:MIRN132 microRNA, human; C546976:MIRN132 microRNA, mouse; C551411:MIRN212 microRNA, human; C554518:MIRN212 microRNA, mouse; D035683:MicroRNAs; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3