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MicroRNA-128 knockout inhibits the development of Alzheimer's disease by targeting PPARγ in mouse models
Yanqiu Liu1, Yuzhen Zhang1, Ping Liu2
1Department of Neurology, PLA 960 Hospital, Zibo, Shandong 255300, China.
Abstract:
Alzheimer's disease (AD) is a great threat for the health and life of elderly people. MicroRNA-128 (miR-128) has been reported to be abnormally expressed in the brain of AD patients and associated with the pathogenesis of AD. Our study aimed to have a deep insight into the roles and molecular basis of miR-128 in the development and progression of AD. The cognitive ability and exploratory behaviors were assessed by morris water maze and open-field tests, respectively. The concentrations of amyloid-β (Aβ) 40, Aβ 42, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 and activity of β-secretase and α-secretase were determined by corresponding ELISA commercial kits. RT-qPCR assay was performed to detect miR-128 level and the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARγ), ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP). Western blot assay was conducted to determine protein expression of PPARγ, amyloid precursor protein (APP), β-APP cleaving enzyme (BACE1), sAPPα and sAPPβ. The effect of miR-128 and PPARγ on amyloid plaque formation was assessed by immunohistochemistry assay. PPARγ mean optical density was determined by immunofluorescence assay. The interaction between miR-128 and PPARγ were validated by bioinformatics analysis and luciferase reporter assay. We found AD mice showed AD-like performance and an increased cerebral cortex Aβ production. MiR-128 expression was upregulated and PPARγ expression was downregulated in cerebral cortex of AD mice. Moreover, PPARγ was a target of miR-128. Additionally, miR-128 knockout or PPARγ upregulation inhibited AD-like performances, amyloid plaque formation, Aβ generation, APP amyloidogenic processing and inflammatory responses in AD mice, while these effects of miR-128 knockout were abrogated by PPARγ inhibitor. The results indicated MiR-128 knockout weakened AD-like performances, and reduced Aβ production and inflammatory responses by targeting PPARγ in AD mice.
Insights
MicroRNA-128 (miR-128) upregulation exacerbates Alzheimer's disease (AD) by downregulating peroxisome proliferator-activated receptor gamma (PPARγ), increasing amyloid-beta production and inflammation. Inhibiting miR-128 or boosting PPARγ ameliorates AD symptoms in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) poses a significant threat to the elderly.
- Abnormal microRNA-128 (miR-128) expression is linked to AD pathogenesis.
- Understanding the molecular mechanisms of miR-128 in AD is crucial.
Purpose of the Study:
- To investigate the role and molecular basis of miR-128 in AD development and progression.
- To elucidate the relationship between miR-128 and peroxisome proliferator-activated receptor gamma (PPARγ) in AD.
- To assess the therapeutic potential of targeting miR-128 or PPARγ.
Main Methods:
- Morris water maze and open-field tests for behavioral assessment.
- ELISA, RT-qPCR, and Western blot for biochemical and molecular analyses.
- Immunohistochemistry, immunofluorescence, bioinformatics, and luciferase reporter assays to validate molecular interactions and effects.
Main Results:
- AD mice exhibited AD-like behaviors and increased cerebral amyloid-beta (Aβ) production.
- miR-128 was upregulated, while PPARγ was downregulated in AD mouse brains.
- miR-128 targeted PPARγ; miR-128 knockout or PPARγ upregulation reduced AD pathology and inflammation.
Conclusions:
- miR-128 upregulation promotes AD progression by inhibiting PPARγ.
- Targeting miR-128 or enhancing PPARγ shows therapeutic promise for Alzheimer's disease.
- The miR-128/PPARγ axis is a key molecular player in AD pathogenesis.