title: The role of STEP in Alzheimer's disease.
abstract: Amyloid beta (Aβ), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Aβ downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP₆₁). More recent findings confirm that STEP₆₁ plays an important role in Aβ-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP₆₁ levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP₆₁ is due to disruption in the normal degradation of STEP₆₁ by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP₆₁ contributes to aspects of the pathophysiology in Alzheimer's disease. Exogenous application of Aβ-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 Aβ treatment.
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Deepa V
authors.initials: DV
authors.lastname: Venkitaramani
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D017397:Prefrontal Cortex; D021381:Protein Transport; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor