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.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disease that leads to dementia and is characterized by extracellular senile plaques, intracellular neurofibrillary tangles and synaptic abnormalities
We found that MAPK phosphatase 1 (MKP-1) transcriptional activation was regulated by specificity protein 1 (Sp1)
We demonstrated that MKP-1 regulated extracellular signal-regulated kinase 1/2 (ERK)/Mitogen-activated protein kinase (MAPK)-mediated Aβ precursor protein (APP) and BACE1 transcriptions, affecting APP processing and Aβ production
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disease that leads to dementia and is characterized by extracellular senile plaques, intracellular neurofibrillary tangles and synaptic abnormalities. In addition to the long-known secretases, recent studies have discovered that APP can be cleaved at a novel cleavage site termed η-site to produce CTF-η,6,7 which is partially mediated by membrane-bound matrix metalloproteinases such as MT5-MMP and is known as η-secretase activity. CTF-η is cleaved by α- and β-secretases to release the long and short Aη peptide, including Aη-α and Aη-β, respectively.[6,8] Previous studies have revealed that Aβ deregulates neurotransmitter release from the presynaptic site in both primary neurons and AD model mouse brains.[9,10,11] Aβ directly interacts with cell membranes and membrane receptors to exert its neurotoxic effect and initiates spine density decrease, synapse loss, and synaptic plasticity impairment,[2,12,13] which may lead to neuronal perturbations and memory decline during AD
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