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MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice
Jianwei Ge1,2,3,4,5, Zhiwei Xue1,2,3,4,5, Shu Shu1,2,3,4,5
1Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School.
Abstract:
Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer's disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-β levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.
Insights
MicroRNA-431 (miR-431) levels decrease in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synaptic plasticity impairment is central to Alzheimer's disease (AD) pathogenesis.
- MicroRNAs (miRs) are emerging as key biomarkers and therapeutic targets for AD-related synaptic dysfunction.
Purpose of the Study:
- To investigate the role of miR-431 in Alzheimer's disease.
- To explore miR-431 as a potential therapeutic target for synaptic deficits in AD.
Main Methods:
- Measured miR-431 levels in plasma and hippocampus of AD patients and APP/PS1 mice.
- Utilized lentivirus-mediated miR-431 overexpression in the hippocampus of APP/PS1 mice.
- Identified and validated Smad4 as a direct target of miR-431.
- Assessed synaptic protein expression and cognitive function.
Main Results:
- miR-431 was significantly downregulated in plasma of patients with mild cognitive impairment and AD, and in the hippocampus and plasma of APP/PS1 mice.
- miR-431 overexpression in APP/PS1 mice improved synaptic plasticity and memory deficits without altering amyloid-beta levels.
- Smad4 knockdown mimicked the protective effects of miR-431, while Smad4 overexpression reversed them, indicating Smad4 is a key mediator.
Conclusions:
- miR-431 plays a protective role against synaptic impairment in Alzheimer's disease.
- The miR-431/Smad4 pathway is a potential therapeutic target for mitigating synaptic dysfunction and memory deficits in AD.
