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Glutamate Receptor Trafficking and Protein Synthesis Mediate the Facilitation of LTP by Secreted Amyloid Precursor Protein-Alpha.
Mockett, Bruce G; Guévremont, Diane; Elder, Megan K; Parfitt, Karen D; Peppercorn, Katie; Morrissey, Jodi; Singh, Anurag; Hintz, Timothy J; Kochen, Lisa; Tom Dieck, Susanne; Schuman, Erin; Tate, Warren P; Williams, Joanna M; Abraham, Wickliffe C.
Afiliação
  • Mockett BG; Department of Psychology.
  • Guévremont D; Department of Anatomy.
  • Elder MK; Department of Anatomy.
  • Parfitt KD; Department of Neuroscience, Pomona College, Claremont, California 91711, and.
  • Peppercorn K; Department of Biochemistry, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand.
  • Morrissey J; Department of Psychology.
  • Singh A; Department of Psychology.
  • Hintz TJ; Department of Psychology.
  • Kochen L; Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
  • Tom Dieck S; Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
  • Schuman E; Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
  • Tate WP; Department of Biochemistry, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand.
  • Williams JM; Department of Anatomy.
  • Abraham WC; Department of Psychology, cabraham@psy.otago.ac.nz.
J Neurosci ; 39(17): 3188-3203, 2019 04 24.
Article em En | MEDLINE | ID: mdl-30804097
ABSTRACT
Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modulate long-term potentiation (LTP) and memory. Here, we demonstrate that exposure to sAPPα converts short-lasting LTP into protein-synthesis-dependent late LTP in hippocampal slices from male rats. sAPPß had no discernable effect. We hypothesized that sAPPα facilitated LTP via regulated glutamate receptor trafficking and de novo protein synthesis. We found using a linear mixed model that sAPPα stimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinase G-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPPα washout and inhibition of receptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA) confirmed the ability of sAPPα to stimulate de novo protein synthesis and revealed GluA1 as one of the upregulated proteins. Therefore, sAPPα generates a coordinated synthesis and trafficking of glutamate receptors to the cell surface that facilitate LTP.SIGNIFICANCE STATEMENT Secreted amyloid precursor protein-alpha (sAPPα) is a neurotrophic and neuroprotective protein that can promote synaptic plasticity and memory, yet the molecular mechanisms underlying these effects are still not well understood. Here, we show that sAPPα facilitates long-term potentiation (LTP) in a concentration-dependent fashion through cellular processes involving de novo protein synthesis and trafficking of both GluA2-lacking AMPARs and NMDARs to the extrasynaptic cell surface. sAPPα also enhances GluA1, but not GluA2, synthesis. The trafficking effects, along with the LTP facilitation, persist after sAPPα washout, revealing a metaplastic capability of exogenous sAPPα administration. sAPPα thus facilitates LTP through coordinated activation of protein synthesis and trafficking of glutamate receptors to the cell surface, where they are positioned for priming LTP.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biossíntese de Proteínas / Precursor de Proteína beta-Amiloide / Receptores de Glutamato / Potenciação de Longa Duração / Hipocampo Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biossíntese de Proteínas / Precursor de Proteína beta-Amiloide / Receptores de Glutamato / Potenciação de Longa Duração / Hipocampo Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article