Int J Biol Sci 2022; 18(5):2220-2234. doi:10.7150/ijbs.66604 This issue

Research Paper

miR-200c suppression increases tau hyperphosphorylation by targeting 14-3-3γ in early stage of 5xFAD mouse model of Alzheimer's disease

Hyunjun Park1,2, Yeong-Bae Lee2,3, Keun-A Chang1,2,4✉

1. Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, 21999, Korea
2. Neuroscience Research Institute, Gachon University, Incheon, 21565, Korea
3. Department of Neurology, Gil Medical Center, College of Medicine, Gachon University, Incheon 21565, Korea
4. Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, Korea

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Citation:
Park H, Lee YB, Chang KA. miR-200c suppression increases tau hyperphosphorylation by targeting 14-3-3γ in early stage of 5xFAD mouse model of Alzheimer's disease. Int J Biol Sci 2022; 18(5):2220-2234. doi:10.7150/ijbs.66604. Available from https://www.ijbs.com/v18p2220.htm

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Abstract

Graphic abstract

Background and Purpose: Recently, several abnormally regulated microRNAs (miRNAs) have been identified in patients with Alzheimer's disease (AD). The purpose of this study was to identify abnormally expressed miRNAs and to investigate whether they affect pathological changes in AD in the 5xFAD AD mouse model.

Experimental Approach: Using microarray analysis and RT-qPCR, miRNA expression in the hippocampus of a 4-month-old 5xFAD mouse model of AD was investigated. A dual-luciferase assay was performed to determine whether the altered miR-200c regulates the translation of the target mRNA, Ywhag. Whether miR-200c modulates AD pathology was determined in primary hippocampal neurons and C57BL/6J mice transfected with miR-200c inhibitor. In addition, total miRNAs were extracted from the serums of 28 healthy age-matched controls and 22 individual participants with cognitive impairment, and RT-qPCR was performed.

Key results: miR-200c expression was reduced in the hippocampus of 5xFAD mice. In primary hippocampal neurons, miR-200c regulated the translation of 14-3-3γ and increased tau phosphorylation (p-tau) by increasing p-GSK-3β (GSK-3β phosphorylation). It was also confirmed that miR-200c inhibition in the hippocampus of C57BL/6J mice induces cognitive impairment and increases tau phosphorylation through 14-3-3γ activation. Finally, aberrant expression of miR-200c was confirmed in the blood serum of human AD patients.

Conclusion and Implications: Our results strongly suggest that dysregulation of miR-200c expression contributes to the pathogenesis of AD, including cognitive impairment through hyperphosphorylated tau.

Keywords: miR-200c, 14-3-3γ, GSK-3β, phosphorylated tau, Alzheimer's disease