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

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 improve cognitive function and hippocampal memory in the 3×Tg-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.