Tyrosine phosphatase STEP sub(61) negatively regulates amyloid [beta]-mediated ERK/CREB signaling pathways via [alpha]7 nicotinic acetylcholine receptors

Striatal-enriched phosphatase 61 (STEP sub(61)) plays an essential role in synaptic plasticity and has recently been implicated in neurodegenerative disease. Here we characterized a possible role of STEP sub(61) 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 [beta] (A[beta]) sub(1-42) peptides]. Our data indicate age-related elevation of STEP sub(61) levels and the proportion of dephosphorylated STEP sub(61) (active STEP sub(61)) in wild-type mice, which was enhanced in APP/PS1 mice. Furthermore, the increased STEP sub(61) levels and active STEP sub(61) were observed in the hippocampus and cortex from 12-month-old APP/PS1 mice and in A[beta] sub(1-42)-treated cortical neurons. An [alpha]7 nicotinic acetylcholine receptors (nAChRs) antagonist, [alpha]-bungarotoxin (BTX), inhibited the A[beta] sub(1-42)-induced increase of STEP sub(61) expression and activation. In addition, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding (CREB) were impaired in A[beta] sub(1-42)-treated cortical neurons, and knockdown of STEP sub(61) enhanced the activation of ERK1/2 and CREB. Collectively, these findings indicate two alternate pathological pathways effecting STEP sub(61) regulation in AD. First, A[beta] regulating STEP sub(61) activity is mediated by A[beta] binding to [alpha]7 nAChRs. Second, STEP sub(61) negatively regulates A[beta]-mediated ERK/CREB pathway, an important signaling cascade involved in memory formation. [copy 2013 Wiley Periodicals, Inc.