Abstract
Accumulation of extracellular amyloid-β (Aβ) in hippocampal subregions is a hallmark of Alzheimer’s disease (AD), which promotes neuronal apoptosis, potentiates cognitive decline and play a causative role in AD pathogenesis. However, whether this process is controlled by distinct miRNAs at the posttranscriptional level remain fascinating but poorly understood. Using post mortem hippocampal samples from human AD patients and 3xTg-AD mouse, we demonstrate that miR-342-3p expression was significantly induced during the AD development. With the aid of intrahippocampal injection of miR-342-3p antagomir, we further show that in vivo miR-342-3p inhibition synergistically improved cognitive deficits in 3xTg-AD mice. The hippocampal Aβ-plaque burden in 3xTg-AD mice, as revealed by immunohistochemical analysis with 4G8 antibody, was attenuated also. Mechanistically, the upregulation of neuronal miR-342-3p is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons in Aβ-challenged HT22 hippocampal neuronal cells. These findings support the model that derangement of hippocampus signal transduction and subsequent neuronal apoptosis in AD arises as a consequence of increased Aβ burden and chronic activation of the JNK MAPK cascade in a miR-342-3p-dependent manner. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant Aβ metabolism pathways in Alzheimer’s disease.
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Supplemental Table 1
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Supplemental Table 2
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Supplemental Fig. 1
Working protocols for the in vivo intrahippocampal injection study. (B) qPCR analyses of miR-342-3p expression in hippocampal tissues of 3xTg-AD mice two months after intrahippocampal injection with miR-342-3p antagomir (n = 10/group). (PDF 95 kb)
Supplemental Fig. 2
Transfection with miR-342-3p mimics or mimics-NC alone exhibits no effects on JNK activation. 48 h after transfection with miR-342-3p mimics or NC, HT22 cells were subjected to Western blot analysis of JNK, p-JNK, c-Jun and p-c-Jun expression levels. (PDF 169 kb)
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Fu, Y., Hu, X., Zheng, C. et al. Intrahippocampal miR-342-3p inhibition reduces β-amyloid plaques and ameliorates learning and memory in Alzheimer’s disease. Metab Brain Dis 34, 1355–1363 (2019). https://doi.org/10.1007/s11011-019-00438-9
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DOI: https://doi.org/10.1007/s11011-019-00438-9