The role of STEP in Alzheimer's disease

Amyloid beta (A beta), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that A beta downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP(61)). More recent findings confirm that STEP(61) plays an important role in A beta-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP(61) levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP(61) is due to disruption in the normal degradation of STEP(61) by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP(61) contributes to aspects of the pathophysiology in Alzheimer's disease. Exogenous application of A beta-enriched conditioned medium (7PA2-CM) to wild-type cortical cultures results in a loss of GluN1/GluN2B subunits from neuronal membranes. Abeta-mediated NMDAR internalization does not occur in STEP knock-out cultures, but is rescued by the addition of active TAT-STEP to the cultures prior to A beta treatment.