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Published on: July 14, 2010
MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer's disease models
Yehong Du1, Yexiang Du2, Yun Zhang3
11Pediatric 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.
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.
Insights
Mitogen-activated protein kinase phosphatase 1 (MKP-1) is reduced in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Mitogen-activated protein kinase (MAPK) signaling pathway dysregulation is linked to Alzheimer's disease (AD).
- Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a key negative regulator of MAPKs, but its role in AD is unclear.
Purpose of the Study:
- To investigate the role of MKP-1 in Alzheimer's disease pathogenesis.
- To explore MKP-1 as a potential therapeutic target for AD.
Main Methods:
- Quantification of MKP-1 levels in human AD brain tissues and an AD mouse model.
- Analysis of MKP-1 gene expression regulation by transcription factor Sp1.
- Investigating the effects of MKP-1 upregulation on amyloid-beta (Aβ) production, APP, and BACE1 expression.
- Assessment of cognitive function and synaptic plasticity in APP/PS1 transgenic mice.
Main Results:
- MKP-1 levels are decreased in the brains of AD patients and an AD mouse model.
- Amyloid-beta (Aβ) induced Sp1 activation, leading to decreased MKP-1 expression.
- Upregulation of MKP-1 inhibited Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 (BACE1) expression by inactivating ERK/MAPK signaling.
- Increased MKP-1 reduced Aβ production, plaque load, and improved cognitive deficits and long-term potentiation (LTP) in APP/PS1 mice.
Conclusions:
- Impaired MKP-1 facilitates Alzheimer's disease (AD) pathogenesis.
- Upregulation of MKP-1 exhibits neuroprotective effects against AD-related phenotypes.
- MKP-1 represents a promising novel therapeutic target for Alzheimer's disease treatment.
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