title: Reduced levels of the tyrosine phosphatase STEP block β amyloid-mediated GluA1/GluA2 receptor internalization.
abstract: Striatal-Enriched protein tyrosine Phosphatase of MW 61 kDa (STEP(61)) is a protein tyrosine phosphatase recently implicated in the pathophysiology of Alzheimer's disease (AD). STEP(61) is elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The elevated levels of active STEP(61) down-regulate surface expression of GluN1/GluN2B (formerly NR1/NR2B) receptor complexes, while genetically reducing STEP levels rescues both the biochemical and cognitive deficits in a triple transgenic AD mouse model (3xTg-AD). Here, we show that increased STEP(61) also plays a role in beta amyloid (Aβ)-mediated internalization of the α-amino-3-hydroxy-5-methyl-4-(AMPA) receptor (AMPAR) subunits GluA1/GluA2 (formerly GluR1/GluR2). We purified Aβ oligomers and determined that oligomers, but not monomers, lead to endocytosis of GluA1/GluA2 receptors in cortical cultures. The decrease in GluA1/GluA2 receptors is reversed in the progeny of STEP knock-out (KO) mice crossed with Tg2576 mice, despite elevated levels of Aβ. These results provide strong support for the hypothesis that STEP(61) is required for Aβ-mediated internalization of GluA1/GluA2 receptors.
authors: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: Yongfang
authors: Y
authors: Zhang
authors: Pradeep
authors: P
authors: Kurup
authors: Jian
authors: J
authors: Xu
authors: George M
authors: GM
authors: Anderson
authors: Paul
authors: P
authors: Greengard
authors: Angus C
authors: AC
authors: Nairn
authors: Paul J
authors: PJ
authors: Lombroso
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis / Q000235:genetics*; D055785:Gene Knockdown Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D018091:Receptors, AMPA; C489930:PTPN5 protein, human; C082101:Ptpn5 protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2