miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease

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 N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. 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-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases

The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses. In this review, we describe the endogenous inflammatory stimulators and signaling pathways in the brain. In particular, our group has focused on the JAK-STAT pathway, identifying anti-inflammatory targets and testing the effects of various anti-inflammatory drugs. This work has shown that the JAK-STAT pathway and its downstream are negatively regulated by phosphatases (SHP2 and MKP-1), inhibitory proteins (SOCS1 and SOCS3) and a nuclear receptor (LXR). These negative regulators are controlled at various levels (e.g. transcriptional, post-transcriptional and post-translational). Future study of these proteins could facilitate the manipulation of the inflammatory response, which plays ubiquitous, diverse and ambivalent roles under physiological and pathological conditions.

Effect of Radix Paeoniae Rubra on intimal proliferation and expression of MKP-1 mRNA after rabbit carotid artery injury / 中华中医药杂志

Objective:To observe the effect of Radix Paeoniae Rubra on intimal proliferation,activating of angiotensin Ⅱ(AgⅡ) and expression of Mitogen-activated protein kinase phosphatase-1(MKP-1) after carotid artery balloon injury in cholesterol-fed rabbits.Methods: Male rabbits were randomly divided into Radix Paeoniae Rubra(PPR) groups: high dose group(75、50、25g.kg-1.d-1;n=8),middle dose group(2g.kg-1.d-1),low dose group(1g.kg-1.d-1;n=8) and control group.Both groups received high fat forage(2% cholesterol + 5% lard).Balloon injury of carotid artery was performed.Carotid artery were harvested at the end of 10 weeks.Expression level of AgⅡwas measured by radioimmunoassay.MKP-1 expression was determined by RT-PCR.Immunohistochemical staining and morphological detection were adopted.Results: Compare with control group,expression of AgⅡ decreased obviously(P

Regulation of MAPK Activity by Seizure-induced MKP-1 in Rat Hippocampus / 신경정신의학

OBJECTIVES: Both electroconvulsive shock(ECS) and kainic acid-induced seizures activate mitogenactivated protein kinases(MAPKs)in rat hippocampus. They can also induce the expression of MAPK phosphatase-1(MKP-1)in rat hippocampus. MKP-1 is known as a specific MAPK deactivator. This study aimed to elucidate the role of MKP-1 in the deactivation of MAPKs in rat hippocampus. METHODS: In order to induce MKP-1 in the hippocampus, ECS was given to the rats. At the time points when MKP-1 was sufficiently induced, the second ECS was given to them and the subsequent phosphorylation or activation of MAPKs were measured in the hippocampus. A second group of rats were injected with kainic acid and the relationship between MKP-1 expression and MAPK phosphorylation was examined in their hippocampi. RESULTS: The expression of MKP-1 did not influence the phosphorylation or activation of MAPKs following ECS in rat hippocampus. Kainic acid-induced expression of MKP-1 did not significantly reduce the phosphorylation of MAPKs. CONCLUSION: MKP-1 did not play a significant role in the deactivation of MAPKs which were activated by ECS or kainic acid in rat hippocampus.