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.

Striatal-enriched protein tyrosine phosphatase modulates nociception

“…4,54 As our results indicated that reduced STEP 61 levels/activity promoted thermal hyperalgesia, we next characterized thermal nociception and STEP 61 levels in the lumbar spinal cord of male and female mice from 3 to 15 months of age. The Hargreaves test showed reduced paw-withdrawal latency with age in males (one-way ANOVA, F (3, 56) = 15.39; P < 0.001; Fig.…”

Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer’s disease

“…Five assays per group. familial model of AD (Xu et al, 2012;Zhang et al, 2013). Furthermore, PTPs may also participate in Ab translocation into lipid rafts.…”

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease

“…Aβ 42 induces the altered conformation of FLNA, and altered FLNA enables sustained Aβ 42 signaling via α7nAChR and TLR4, possibly by securing high affinity binding of Aβ [13,15] . Aβ 42 's toxic signaling via α7nAChR activates kinases to hyperphosphorylate tau [25][26][27][28][29][30][31] , leading to its dysfunction and aggregation, and the FLNA-enabled Aβ 42 activation of TLR4 enhances neuroinflammation [13,15] . Moreover, the altered conformation of FLNA is an important catalyst of Aβ toxicities and tau dysfunction, including neuroinflammation and synaptic dysfunction.…”

“…Extensive research has elucidated the role of the α7nAChR in the toxicity of soluble Aβ 42 and the consequent hyperphosphorylation of tau [19][20][21][22][23][24] . Soluble Aβ 42 in monomeric or oligomeric form binds and signals via α7nAChR [25][26][27][28] , essentially hijacking this receptor to abnormally activate various kinases [27,[29][30][31] to heighten tau phosphorylation. Supportive data include co-localization of Aβ 42 and α7nAChR in AD pyramidal neurons and a complete blockade of Aβ 42 -induced tau hyperphosphorylation in vitro by α7nAChR antisense oligonucleotides [32] .…”