MiR‐431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice

Abstract

AbstractBackgroundSynaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. Our previous miRNA assay data have shown that miR‐431 is downregulated in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. However, the potential role of miR‐431 in AD has not been fully defined.MethodLv‐miR‐431 (1×109 TU/ml, 2 µl), Lv‐Smad4 (1×109 TU/ml, 2 µl) or AAV‐sh‐Smad4 (5×1012 GC/ml, 200 nl) was slowly injected into the bilateral hippocampus of APP/PS1 mice. The behavioral or electrophysiological tests were performed 1 month following the injection, and the mice were then sacrificed for other experiments. QRT‐PCR was used to detect the expression of miR‐431 in plasma and hippocampus. Golgi staining and electron microscopy were performed to evaluate the synaptic structure. Western blot was employed to test the levels of synaptic associated proteins. Immunofluorescence staining and ELISA were utilized to assess hippocampal Aβ levels. Cut&Tag assay and ChIP were used to explore and confirm the potential targets of Smad4.ResultThe level of miR‐431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients, and it was also decreased in the hippocampus and plasma of APP/PS1 mice. MiR‐431 overexpression in the hippocampus ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn’t affect the Aβ levels. Smad4 was identified as a target of miR‐431, and Smad4 overexpression reversed the protective effects of miR‐431 in APP/PS1 mice. Furthermore, Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice.ConclusionMiR‐431 attenuates synaptic impairment at least partially by Smad4 inhibition and miR‐431/Smad4 may be a potential therapeutic target for AD treatment.