miR-485-5p alleviates Alzheimer's disease progression by targeting PACS1
Chuan He1, Caixia Su1, Wentong Zhang1
1Department of Rehabilitation Medicine, Jiangsu-Shengze Hospital affiliated to Nanjing Medical University, Suzhou 215228, Jiangsu, China.
Abstract:
Alzheimer's disease (AD) is a common dementia and a heterogeneous disease. Previous research has validated that microRNAs (miRNAs) are pivotal regulators in the initiation and development of tremendous diseases including AD. MicroRNA-485-5p (miR-485-5p) was reported to be an important participant implicated in several neurological diseases, but its role in AD still needs to be further investigated. In this research, we explored the biological function of miR-485-5p in AD. RT-qPCR revealed that miR-485-5p expression was downregulated in the hippocampus of APP/PS1 mice. Additionally, miR-485-5p overexpression facilitated the learning and memory capabilities of APP/PS1 mice according to Morris water maze test, fear conditioning test, and immunofluorescent staining. Moreover, CCK-8 assay, flow cytometric analysis, and western blot analysis suggested that miR-485-5p overexpression promoted pericyte viability and prohibited pericyte apoptosis in APP/PS1 mice. Mechanistically, miR-485-5p directly targeted PACS1 in pericytes, as shown in a luciferase reporter assay. In rescue assays, PACS1 overexpression countervailed the effect of miR-485-5p overexpression on pericyte viability and apoptosis. In conclusion, miR-485-5p ameliorates AD progression by targeting PACS1.
Insights
MicroRNA-485-5p (miR-485-5p) is downregulated in Alzheimer's disease (AD) mouse models. Overexpressing miR-485-5p improves memory and protects pericytes by targeting PACS1, suggesting a therapeutic role in AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is a complex neurodegenerative disorder with significant unmet therapeutic needs.
- MicroRNAs (miRNAs) are key regulators in disease pathogenesis, including AD.
- The specific role of microRNA-485-5p (miR-485-5p) in AD progression remained largely unexplored.
Purpose of the Study:
- To investigate the function and mechanism of miR-485-5p in Alzheimer's disease.
- To determine the expression levels of miR-485-5p in an AD mouse model.
- To elucidate the downstream targets and cellular effects of miR-485-5p in the context of AD.
Main Methods:
- Quantitative real-time PCR (RT-qPCR) to measure miR-485-5p expression in the hippocampus of APP/PS1 mice.
- Behavioral tests (Morris water maze, fear conditioning) and immunofluorescent staining to assess learning and memory.
- Cell viability (CCK-8 assay), apoptosis (flow cytometry), and protein expression (Western blot) analyses in pericytes.
- Luciferase reporter assays to confirm direct targeting of PACS1 by miR-485-5p.
- Rescue experiments with PACS1 overexpression to validate the mechanism.
Main Results:
- miR-485-5p expression was significantly downregulated in the hippocampus of APP/PS1 mice.
- Overexpression of miR-485-5p enhanced cognitive functions, including learning and memory, in APP/PS1 mice.
- miR-485-5p promoted pericyte viability and inhibited apoptosis in the AD model.
- PACS1 was identified as a direct target of miR-485-5p in pericytes.
- Overexpression of PACS1 reversed the protective effects of miR-485-5p on pericytes.
Conclusions:
- miR-485-5p plays a neuroprotective role in Alzheimer's disease.
- The mechanism involves the direct targeting of PACS1, leading to improved pericyte function and cognitive enhancement.
- miR-485-5p represents a potential therapeutic target for ameliorating Alzheimer's disease progression.
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