Journal
THERANOSTICS
Volume 11, Issue 5, Pages 2395-2409Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.47408
Keywords
A beta plaques; Alzheimer's Disease; autophagy; microglia; microRNA
Categories
Funding
- National Natural Science Foundation of China [81974127, 81701383, 31700680, 81522012, 81670807, 81871822, 81702237, 81802138, 81801395, 81600699]
- Guangdong Basic and Applied Basic Research Foundation [2016A030306051, 2017A030310005]
- Innovation-Driven Project of Central South University [2018CX029, 2019CX014]
- Science and Technology Plan Project of Hunan Province [2018RS3029, 2017XK2039]
- Shenzhen Foundation of Science and Technology [JCYJ20170306092009689]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019-RC-HL-024]
- China Postdoctoral Science Foundation [2017M612596, 2019T120717, 2018M63 2998, 2020T130142ZX]
- Fundamental Research Funds for the Central Universities of Central South University [2019zzts1042]
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The study found biphasic changes of miR-331-3p and miR-9-5p in AD progression, inhibiting these two microRNAs can promote autophagic clearance of A beta and prevent AD development. This was demonstrated in experiments and offers a potential new therapeutic strategy for AD patients.
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 (A beta). 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 A beta levels, neuron numbers (MAP(2+)) 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 A beta 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 A beta 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.
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