Striatal-enriched phosphatase 61 (STEP61 ) plays an essential role in synaptic plasticity and has recently been implicated in neurodegenerative disease. Here we characterized a possible role of STEP61 in Alzheimer's disease (AD) pathology using a mouse model of AD (Tg-APPswe/PSEN1dE9, APP/PS1 mice) and an in vitro model of AD [cortical neurons treated with amyloid β (Aβ)1-42 peptides]. Our data indicate age-related elevation of STEP61 levels and the proportion of dephosphorylated STEP61 (active STEP61 ) in wild-type mice, which was enhanced in APP/PS1 mice. Furthermore, the increased STEP61 levels and active STEP61 were observed in the hippocampus and cortex from 12-month-old APP/PS1 mice and in Aβ1-42 -treated cortical neurons. An α7 nicotinic acetylcholine receptors (nAChRs) antagonist, α-bungarotoxin (BTX), inhibited the Aβ1-42 -induced increase of STEP61 expression and activation. In addition, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding (CREB) were impaired in Aβ1-42 -treated cortical neurons, and knockdown of STEP61 enhanced the activation of ERK1/2 and CREB. Collectively, these findings indicate two alternate pathological pathways effecting STEP61 regulation in AD. First, Aβ regulating STEP61 activity is mediated by Aβ binding to α7 nAChRs. Second, STEP61 negatively regulates Aβ-mediated ERK/CREB pathway, an important signaling cascade involved in memory formation.
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http://dx.doi.org/10.1002/jnr.23263 | DOI Listing |
ACS Chem Neurosci
September 2023
Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has been confirmed to contribute to brain injury in ischemic stroke via promoting excitotoxicity and necroptosis. Telaprevir, a hepatitis C virus protease inhibitor, is predicted to be a potential MALT1 inhibitor. Here, we showed that telaprevir protected against cerebral ischemic injury via inhibiting MALT1, thereby preventing glutamate receptor ionotropic NMDA 2B (GluN2B) activation, limiting calcium overload, and suppressing necroptosis.
View Article and Find Full Text PDFJ Neurochem
July 2023
Department of Pathophysiology, Neuroscience Research Center, Hebei Medical University, Shijiazhuang City, People's Republic of China.
Abnormal activation of the extrasynaptic N-methyl-d-aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by upregulating glutamate transporter-1 and promoting the glutamate-glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive-behavioral impairment and to unravel the associated underlying mechanisms.
View Article and Find Full Text PDFCell Mol Neurobiol
October 2023
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai, 400019, India.
STEP (STriatal-Enriched Protein Tyrosine Phosphatase) is a brain-specific phosphatase that plays an important role in controlling signaling molecules involved in neuronal activity and synaptic development. The striatum is the main location of the STEP enzyme. An imbalance in STEP61 activity is a risk factor for Alzheimer's disease (AD).
View Article and Find Full Text PDFMol Brain
January 2023
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St. Lucia Campus, Brisbane, QLD, Australia.
Synaptic degeneration is a precursor of synaptic and neuronal loss in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia with tau pathology (FTD-tau), a group of primary tauopathies. A critical role in this degenerative process is assumed by enzymes such as the kinase Fyn and its counterpart, the phosphatase striatal-enriched tyrosine phosphatase 61 (STEP). Whereas the role of Fyn has been widely explored, less is known about STEP that localises to the postsynaptic density (PSD) of glutamatergic neurons.
View Article and Find Full Text PDFMol Neurobiol
March 2023
Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
Glutamate receptor ionotropic NMDA 2B (GluN2B) plays an essential role in calcium overload during excitotoxicity. Reverse-phase nano-liquid chromatography-tandem mass spectrometry has revealed an interaction between GluN2B and HECT domain E3 ubiquitin protein ligase 4 (HECTD4), an E3 ubiquitin ligase highly expressed in the brain. As a potential substrate for HECTD4, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) acts as a scaffold with hydrolysis activity.
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