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 6

Smad4 inhibition alleviates memory deficits in 6-month-old APP/PS1 mice.

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Smad4 inhibition alleviates memory deficits in 6-month-old APP/PS1 mice....
(A) A representative fluorescence image of the AAV-con-infected and AAV-sh-Smad4-infected slice. Left panel, bar = 1,000 μm, right panel, bar = 200 μm. The mRNA (B) and protein (C and D) levels of Smad4 in the hippocampus after AAV-sh-Smad4 treatment. n = 4 for mRNA level and n = 3 for protein level. (E) The time exploring the objects was recorded by a visual tracking system in the NOR tests. F (2, 39) = 3.644, P = 0.0352. (F) The freezing time in contextual FC tests was recorded. F (2, 39) = 7.391, P = 0.0019. Escape latency (G) [groups: F (4, 195) = 14.62, P < 0.0001; days: F (2, 195) = 16.16, P < 0.0001; group × day: F (8, 195) = 0.7725, P = 0.6274] was detected in the acquisition trial. The swimming speed (H) [F (2, 39) = 0.2675, P = 0.7667], representative swimming paths (I), crossing platform times (J) [F (2, 39) = 5.311, P = 0.0091], time spent in target quadrant (K) [F (2, 39) = 4.811, P = 0.0136], and latency to target quadrant (L) [F (2, 39) = 4.203, P = 0.0222] were recorded in the probe trial in the MWM tests. n = 14. *P < 0.05, **P < 0.01 vs. AAV-WT group; #P < 0.05, ###P < 0.001 vs. AAV-con group. All data were presented as means ± SEM. Two-tailed unpaired Student’s t test (B and D), 1-way ANOVA (E, F, H, and J–L), and 2-way ANOVA (G) were used.