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

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.

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease

“…The Morris water maze consists of a circular stainless steel pool (150 cm in diameter) filled with opaque white paint as previously described (Dong et al, ; Du et al, ). The pool was surrounded by light blue curtains, and 3 distal visual cues were fixed to the curtains.…”

“…Mice (4 months old) were deeply anesthetized with urethane (1.5 g/kg, i.p.) and transcardially perfused with artificial cerebral spinal fluid (ACSF) (in mM: NaCl 124, KCl 2.8, NaH 2 PO 4 .H 2 O 1.25, CaCl 2 2.0, MgSO 4 1.2, Na‐vitamin C 0.4, NaHCO 3 26, Na‐lactate 2.0, Na‐pyruvate 2.0 and D‐glucose 10.0, pH = 7.4) prior to decapitation as described previously (Du et al, ; Huang et al, ). Then, hippocampal slices were coronally sectioned (400 μm) with a vibratome (VT1200S, Leica Microsystems, Bannockburn, IL) with 95% O 2 and 5% CO 2 , and then were incubated in ACSF for 2 hr at 35°C.…”

“…Sections were mounted onto slides, and plaques were visualized by the ABC and DAB method and counted by microscopy at ×40 magnification. The mean plaque count per slice was recorded for each mouse as described previously (Dong et al, ; Du et al, ).…”

“…β‐actin was the internal reference. The band intensity of each protein was quantified by the Bio‐Rad Quantity One software as described previously (Dong et al, ; Du et al, ).…”

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

“…This result is consistent with past ndings where the brain's immune system has been indicated as a major component of AD pathogenesis 56,57 . Additionally, MAPKs, enzymes that play critical roles in cellular signaling, have also been implicated as accelerators of AD development 58 . Overall, ndings from our brain transcriptome analysis provide supporting evidence for therapeutics currently being explored for AD, such as p38 MAPK inhibitors 59 , and suggest that possible treatments targeting the MAPK pathway may have a greater effect in females with AD.…”