The role of STEP in Alzheimer's disease.
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.
Kurup
Pradeep
P
Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
Zhang
Yongfang
Y
Venkitaramani
Deepa V
DV
Xu
Jian
J
Lombroso
Paul J
PJ
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
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