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.
10.1016/j.apsb.2023.10.015
- Author:
Man LUO
1
;
Yayan PANG
1
;
Junjie LI
1
;
Lilin YI
1
;
Bin WU
1
;
Qiuyun TIAN
1
;
Yan HE
1
;
Maoju WANG
1
;
Lei XIA
1
;
Guiqiong HE
2
;
Weihong SONG
1
;
Yehong DU
1
;
Zhifang DONG
1
Author Information
1. Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
2. Department of Anatomy, Basic Medical College, Chongqing Medical University, Chongqing 400016, China.
- Publication Type:Journal Article
- Keywords:
AMPA receptor;
Alzheimer's disease;
Learning and memory;
Long-term potentiation;
MKP-1;
miR-429-3p
- From:
Acta Pharmaceutica Sinica B
2024;14(2):635-652
- CountryChina
- Language:English
-
Abstract:
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.
