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

Man Luo; Yayan Pang; Junjie Li; Lilin Yi; Bin Wu; Qiuyun Tian; Yan He; Maoju Wang; Lei Xia; Guiqiong He; Weihong Song; Yehong Du; Zhifang Dong

doi:10.1016/j.apsb.2023.10.015

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

Acta Pharm Sin B. 2024 Feb;14(2):635-652. doi: 10.1016/j.apsb.2023.10.015. Epub 2023 Oct 28.

Authors

Man Luo¹, Yayan Pang¹, Junjie Li¹, Lilin Yi¹, Bin Wu¹, Qiuyun Tian¹, Yan He¹, Maoju Wang¹, Lei Xia¹, Guiqiong He², Weihong Song^{1

3

4}, Yehong Du¹, Zhifang Dong^{1

5}

Affiliations

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.
³ Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver BC V6T 1Z3, Canada.
⁴ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and the Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou 325000, China.
⁵ Institute for Brain Science and Disease of Chongqing Medical University, Chongqing 400016, China.

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 N2A^APP 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.

Keywords: AMPA receptor; Alzheimer's disease; Learning and memory; Long-term potentiation; MKP-1; miR-429-3p.