miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression.

Abstract

MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model. In the prefrontal cortices of double knockout mice, miR-125b was found to be abnormally increased in an age-dependent manner. We further verified the neural cell adhesion molecule (NCAM) as an miR-125b target using the dual luciferase reporter assay. The NCAM protein level was decreased when miR-125b was overexpressed (OE) in neuronal growth factor-induced differentiated PC12 cells, which further inhibited the neuronal growth factor-induced phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at the Ser9 site and ultimately increased the GSK3β activity and tau phosphorylation. Moreover, on serum deprivation, high GSK3β activity in differentiated miR-125b-OE PC12 cells induced increased caspase-3 activation. Finally, adeno-associated virus-mediated miR-125b overexpression in the prefrontal cortexes of wild-type C57B/L6 mice resulted in decreased dendritic spine density. In addition, similar to the in vitro data, elevated GSK3β activity and hyperphosphorylation of the tau protein were confirmed. Taken together, our findings reveal a direct regulation of miR-125b on NCAM, which leads to further effects on downstream GSK3β activity and tau phosphorylation and may contribute to the generation of neurofibrillary tangles in neuropathological progression.

• Authors: Linyu Zhang, Hao Dong, Youwen Si, Nan Wu, Hao Cao, Bing Mei, Bo Meng
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 73 Pg. 41-49 (01 2019) ISSN: 1558-1497 [Electronic] United States
• PMID: 30316051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• Mirn125 microRNA, mouse
• Neural Cell Adhesion Molecules
• tau Proteins
• Glycogen Synthase Kinase 3 beta

Topics

• Aging (genetics, metabolism)
• Animals
• Cells, Cultured
• Dementia (genetics, pathology)
• Dendritic Spines (pathology)
• Disease Progression
• Gene Expression
• Gene Expression Regulation, Developmental
• Glycogen Synthase Kinase 3 beta (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, physiology)
• Neural Cell Adhesion Molecules (metabolism)
• Neurofibrillary Tangles (genetics, pathology)
• PC12 Cells
• Phosphorylation (genetics)
• Prefrontal Cortex (metabolism)
• Rats
• tau Proteins (metabolism)