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

被引：208

作者：

Smith, Pascal Y. ^{[1
,2
]}

Hernandez-Rapp, Julia ^{[1
,2
]}

Jolivette, Francis ^{[1
,2
]}

Lecours, Cynthia ^{[1
,3
]}

Bisht, Kanchan ^{[1
,3
]}

Goupil, Claudia ^{[1
,2
]}

Dorval, Veronique ^{[1
,2
]}

Parsi, Sepideh ^{[1
,2
]}

Morin, Francoise ^{[1
,2
]}

Planel, Emmanuel ^{[1
,2
]}

Bennett, David A. ^{[5
]}

Fernandez-Gomez, Francisco-Jose ^{[6
,7
]}

Sergeant, Nicolas ^{[6
,7
]}

Buee, Luc ^{[6
,7
]}

Tremblay, Marie-Eve ^{[1
,3
]}

Calon, Frederic ^{[1
,4
]}

Hebert, Sebastien S. ^{[1
,2
]}

机构：

[1] CHU Quebec, CHUL, Ctr Rech, Axe Neurosci, Quebec City, PQ G1V 4G2, Canada

[2] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ G1V 0A6, Canada

[3] Univ Laval, Dept Mol Med, Quebec City, PQ G1V 0A6, Canada

[4] Univ Laval, Fac Pharm, Quebec City, PQ G1V 0A6, Canada

[5] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[6] Univ Lille, Fac Med, UDSL, F-59045 Lille, France

[7] INSERM, UMR S 1172, Alzheimer & Tauopathies, F-59045 Lille, France

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 23期

基金：

加拿大健康研究院;

关键词：

MILD COGNITIVE IMPAIRMENT; PLASMA MICRORNA BIOMARKERS; ALZHEIMERS-DISEASE; FRONTOTEMPORAL DEMENTIA; A-BETA; HUNTINGTONS-DISEASE; PROTEIN PATHOLOGY; 3XTG-AD MICE; MAPT GENE; EXPRESSION;

D O I：

10.1093/hmg/ddv377

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-3 beta 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.

引用

页码：6721 / 6735

页数：15

共 90 条

[1] MicroRNAs and neurodegeneration: role and impact [J].