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International Journal of Biological Sciences
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Theranostics 2021; 11(5):2395-2409. doi:10.7150/thno.47408 This issue Cite
Research Paper
Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy
1. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
2. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
3. Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
4. Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China.
5. Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China.
6. Xiangya Nursing School, Central South University, Changsha, Hunan 410013, China.
7. Institue of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
8. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
9. Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, China.
Citation:
Chen ML, Hong CG, Yue T, Li HM, Duan R, Hu WB, Cao J, Wang ZX, Chen CY, Hu XK, Wu B, Liu HM, Tan YJ, Liu JH, Luo ZW, Zhang Y, Rao SS, Luo MJ, Yin H, Wang YY, Xia K, Tang SY, Xie H, Liu ZZ. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics 2021; 11(5):2395-2409. doi:10.7150/thno.47408. https://www.thno.org/v11p2395.htm
Other stylesAbstract
Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ).
Methods: The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2+) and activated microglia (CD68+IBA1+) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (Becn1, Sqstm1, LC3b) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined.
Results: MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (Sqstm1) and Optineurin (Optn), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage.
Conclusion: Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.
Keywords: Aβ plaques, Alzheimer's Disease, autophagy, microglia, microRNA
Citation styles
APA
Chen, M.L., Hong, C.G., Yue, T., Li, H.M., Duan, R., Hu, W.B., Cao, J., Wang, Z.X., Chen, C.Y., Hu, X.K., Wu, B., Liu, H.M., Tan, Y.J., Liu, J.H., Luo, Z.W., Zhang, Y., Rao, S.S., Luo, M.J., Yin, H., Wang, Y.Y., Xia, K., Tang, S.Y., Xie, H., Liu, Z.Z. (2021). Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics, 11(5), 2395-2409. https://doi.org/10.7150/thno.47408.
ACS
Chen, M.L.; Hong, C.G.; Yue, T.; Li, H.M.; Duan, R.; Hu, W.B.; Cao, J.; Wang, Z.X.; Chen, C.Y.; Hu, X.K.; Wu, B.; Liu, H.M.; Tan, Y.J.; Liu, J.H.; Luo, Z.W.; Zhang, Y.; Rao, S.S.; Luo, M.J.; Yin, H.; Wang, Y.Y.; Xia, K.; Tang, S.Y.; Xie, H.; Liu, Z.Z. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics 2021, 11 (5), 2395-2409. DOI: 10.7150/thno.47408.
NLM
Chen ML, Hong CG, Yue T, Li HM, Duan R, Hu WB, Cao J, Wang ZX, Chen CY, Hu XK, Wu B, Liu HM, Tan YJ, Liu JH, Luo ZW, Zhang Y, Rao SS, Luo MJ, Yin H, Wang YY, Xia K, Tang SY, Xie H, Liu ZZ. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics 2021; 11(5):2395-2409. doi:10.7150/thno.47408. https://www.thno.org/v11p2395.htm
CSE
Chen ML, Hong CG, Yue T, Li HM, Duan R, Hu WB, Cao J, Wang ZX, Chen CY, Hu XK, Wu B, Liu HM, Tan YJ, Liu JH, Luo ZW, Zhang Y, Rao SS, Luo MJ, Yin H, Wang YY, Xia K, Tang SY, Xie H, Liu ZZ. 2021. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics. 11(5):2395-2409.
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