miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.

TitlemiR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.
Publication TypeJournal Article
Year of Publication2015
AuteursSmith, PY, Hernandez-Rapp, J, Jolivette, F, Lecours, C, Bisht, K, Goupil, C, Dorval, V, Parsi, S, Morin, F, Planel, E, Bennett, DA, Fernandez-Gomez, F-J, Sergeant, N, Buée, L, Tremblay, M-È, Calon, F, Hébert, SS
JournalHum Mol Genet
Date Published2015 Dec 01
KeywordsAnimals, Cognition Disorders, Disease Models, Animal, Down-Regulation, Gene Expression Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Mice, MicroRNAs, Phosphorylation, Protein Aggregation, Pathological, tau Proteins, Tauopathies

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.

Alternate JournalHum. Mol. Genet.
PubMed ID26362250
PubMed Central IDPMC4634376
Grant List00892-000 / / Canadian Institutes of Health Research / Canada
RF1 AG015819 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
RF1AG15819 / AG / NIA NIH HHS / United States