MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice
Jianwei Ge, Zhiwei Xue, Shu Shu, Linjie Yu, Ruomeng Qin, Wenyuan Tao, Pinyi Liu, Xiaohong Dong, Zhen Lan, Xinyu Bao, Lei Ye, Yun Xu, Xiaolei Zhu
Jianwei Ge, Zhiwei Xue, Shu Shu, Linjie Yu, Ruomeng Qin, Wenyuan Tao, Pinyi Liu, Xiaohong Dong, Zhen Lan, Xinyu Bao, Lei Ye, Yun Xu, Xiaolei Zhu
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Research Article Aging Therapeutics

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

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.

Authors

Jianwei Ge, Zhiwei Xue, Shu Shu, Linjie Yu, Ruomeng Qin, Wenyuan Tao, Pinyi Liu, Xiaohong Dong, Zhen Lan, Xinyu Bao, Lei Ye, Yun Xu, Xiaolei Zhu

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Figure 3

MiR-431 does not affect Aβ levels in the hippocampus of 6-month-old APP/PS1 mice.

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MiR-431 does not affect Aβ levels in the hippocampus of 6-month-old APP/...
(A) The level of Aβ 6e10 in the hippocampus of Lv-miR-431–treated APP/PS1 mice was detected by immunofluorescence staining. (B) The level of Aβ 82e1 in the hippocampus of Lv-miR-431–treated APP/PS1 mice. Bars = 100 μm. (C) Quantitative analysis of the percentage of Aβ 6e10–positive area. n = 4 mice per group. Bar = 200 μm. (D) Quantitative analysis of the percentage of Aβ 82e1–positive area. n = 4 mice per group. Bar = 200 μm. The protein levels of TBS-soluble, TBS-T–soluble, and FA-soluble Aβ40 (E) and Aβ42 (F) were measured by ELISA in the hippocampus of Lv-miR-431–treated APP/PS1 mice. n = 3, NS. All data were presented as means ± SEM. Two-tailed unpaired Student’s t test (C and D) and 2-way ANOVA (E and F) were used. TBS-T, TBS-Tween; FA, formic acid.