title: Tyrosine phosphatase STEP61 negatively regulates amyloid β-mediated ERK/CREB signaling pathways via α7 nicotinic acetylcholine receptors.
abstract: 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.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xie
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Cao
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D064569:alpha7 Nicotinic Acetylcholine Receptor; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse
keywords: Alzheimer's disease; RNA interference; STEP61; pCREB; pERK1/2; α7 AChR; β-amyloid peptide