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 5

Smad4 is a target of miR-431.

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Smad4 is a target of miR-431. (A) TargetScan prediction of the binding s...
(A) TargetScan prediction of the binding sites of miR-431 with Smad4 3′-UTR. (B) HEK293T cells were infected by Lv-miR-431 for 72 hours followed by transfecting with Smad4 3′-UTR or mutant Smad4 3′-UTR for another 24 hours, and relative luciferase activity was determined. n = 4. The mRNA (C) and protein levels (D and E) of Smad4 in Lv-miR-431–treated primary neurons. n = 4. The mRNA (F) and protein (G and H) levels of Smad4 in the hippocampus after Lv-miR-431 treatment. n = 3. *P < 0.05, **P < 0.01 vs. Lv-con group. (I) The mRNA level of Smad4 in the hippocampus of 3-, 6-, 9-, and 12-month-old APP/PS1 mice. n = 6–8 for each group. (J) The expression correlation of miR-431 and Smad4 mRNA level in WT and APP/PS1 mice as shown in panel. n = 58. (K and L) The protein level of Smad4 in the hippocampus of 6-month-old WT and APP/PS1 mice. n = 3. *P < 0.05, **P < 0.01 vs. WT group. (M) The I/O slope of hippocampal CA1 in Lv-miR-431– and Lv-Smad4–treated APP/PS1 mice. (N and O) High-frequency induced LTP stimulation was observed in hippocampal CA1 area. F (2, 6) = 6.858, P = 0.0282, n = 3 mice per group. *P < 0.05, ***P < 0.001 vs. Lv-con+Lv-con2 group; #P < 0.05, ###P < 0.001 vs. Lv-miR-431+Lv-con2 group. All data were presented as means ± SEM. Two-way ANOVA (B, I, and M), 2-tailed unpaired Student’s t test (C, E, F, H, and L), Pearson’s correlation (J), and 1-way ANOVA (N and O) were used.