MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

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Abstract

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.

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Most cited references 62

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SUMMARY Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrPC) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrPC is enriched in post-synaptic densities, and Aβ/PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrPC to activate Fyn. Aβ engagement of PrPC/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrPC and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway requiring PrPC and Fyn to alter synaptic function with relevance to AD.

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Author and article information

Contributors

Weihong Song: weihong@mail.ubc.ca

Guiqiong He: guiqionghe@hotmail.com

Zhifang Dong: zfdong@cqmu.edu.cn

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 6 December 2019

Publication date PMC-release: 6 December 2019

Publication date Collection: 2019

Volume: 4

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, 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 PR China

[2 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Department of Anatomy, Basic Medical College, , Chongqing Medical University, ; Chongqing, 400016 PR China

[3 ]ISNI 0000 0001 2288 9830, GRID grid.17091.3e, Townsend Family Laboratories, Department of Psychiatry, , The University of British Columbia, ; Vancouver, BC V6T 1Z3 Canada

[4 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, West China School of Basic Medical Sciences and Forensic Medicine, , Sichuan University, ; Chengdu, 610041 Sichuan China

[5 ]ISNI 0000 0001 2288 9830, GRID grid.17091.3e, Brain Research Centre, , The University of British Columbia, ; Vancouver, BC V6T 2B5 Canada

Article

Publisher ID: 91

DOI: 10.1038/s41392-019-0091-4

PMC ID: 6895219

PubMed ID: 31840000

SO-VID: ac4db4e3-e3be-4e93-b38d-26cc7d77f8f0

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 29 August 2019

Date revision received : 1 November 2019

Date accepted : 1 November 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 91749116

Award ID: 81622015

Award ID: 81671257

Award Recipient : Guiqiong He Zhifang Dong

Funded by: the Science and Technology Research Program of Chongqing Municipal Education Commission (grant No. KJZD-K201900403) and Innovation Research Group at Institutions of Higher Education in Chongqing (grant No. CXQTP19019019034).