miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1containing AMPA receptors in a mouse model of Alzheimer's disease
miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1containing AMPA receptors in a mouse model of Alzheimer's disease
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DOI：
10.1016/j.apsb.2023.10.015
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发表时间：
2024-01-27
影响因子：
14.5
通讯作者：
Dong，Zhifang
中科院分区：
文献类型：
--
作者：
Luo，Man;Pang，Yayan;Dong，Zhifang
阿尔茨海默病（AD）是老年人痴呆症的主要原因。丝裂原活化蛋白激酶磷酸酶1（MKP-1）在AD中起神经保护作用。然而，MKP-1对AD作用的分子机制尚未得到广泛研究。microRNA（miRNAs）在转录后水平调节基因表达，从而抑制mRNA翻译。在此，我们报道了microRNA-429- 3 p（miR-429- 3 p）在APP 23/PS45 AD模型小鼠和N2 AAPPAD模型细胞的脑中显著增加。我们进一步发现miR-429- 3 p可通过直接与MKP-1的3′非翻译区（3′ UTR）结合而下调MKP-1的表达。miR-429- 3 p的抑制剂A-miR-429可使MKP-1的表达恢复到对照水平，从而减少APP的淀粉样加工和Aβ积累。更重要的是，A-miR-429鼻内给药通过抑制细胞外信号调节激酶（ERK 1/2）介导的GluA 1 Ser 831位点过度磷酸化，从而增加含GluA 1的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表面表达，成功改善了AD模型小鼠海马CA 1长时程增强和空间学习记忆的缺陷。总之，这些结果表明，上调miR-429- 3 p以上调MKP-1可有效改善AD模型小鼠的认知和突触功能，提示miR-429/MKP-1通路可能成为AD治疗的新靶点。
Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model cells. We further found thatmiR-429-3pcould downregulate MKP-1 expression by directly binding to its 3′-untranslated region (3′ UTR). Inhibition ofmiR-429-3pby its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβaccumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containingα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibitingmiR-429-3pto upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting thatmiR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.