STEP inhibition prevents Aβ-mediated damage in dendritic complexity and spine density in Alzheimer’s disease.

Abstract

Loss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimer's disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2 and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improves cognitive function and hippocampal memory in the 3xTg AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent. Abbreviations STEP = STriatal-Enriched protein tyrosine Phosphatase AD = Alzheimer's disease 3xTg = triple transgenic mouse model CM = conditioned medium CNS = central nervous system ANOVA = analysis of variance Aβ = beta amyloid GluN2B = glutamate ionotropic receptor NMDA type subunit 2B GluA2 = glutamate ionotropic receptor AMPA type subunit 2 Pyk2 = protein tyrosine kinase 2 ERK1/2 = extracellular signal-regulated kinase-1 SPIN90 = SH3 protein interacting with Nck, 90 kDa WT = wild-type

Inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity reverses behavioral deficits in a rodent model of autism

“…In addition, STEP dephosphorylation of the ionotropic glutamate receptor subunits GluN2B and GluA2 results in internalization of NMDA and AMPA receptor complexes [15,16]. In addition, STEP also plays a role in spine dynamics by dephosphorylating SPIN90 [17,18].…”