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

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 Aβprecursor protein(APP)andβ-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2(ERK)/MAPK signaling pathway.Furthermore,upregulation of MKP-1 reduced Aβproduction 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.