Article Dans Une Revue Aging Cell Année : 2023

Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein

Joana Rajão‐saraiva
Jade Dunot
  • Fonction : Auteur
Aurore Ribera
  • Fonction : Auteur
Mariana Temido-Ferreira
  • Fonction : Auteur
Joana E Coelho
  • Fonction : Auteur
Svenja König
  • Fonction : Auteur
Sébastien Moreno
  • Fonction : Auteur
Francisco J Enguita
  • Fonction : Auteur
Michael Willem
  • Fonction : Auteur
Stefan Kins
  • Fonction : Auteur
Luísa V Lopes
Paula A Pousinha

Résumé

Abstract N‐methyl‐D‐aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch‐clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B‐NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B‐NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic‐derived C‐terminal fragments, rather than APP full‐length, contribute to aberrant GluN2B‐NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain. Interfering with stability or production of the APP intracellular domain normalized the GluN2B‐NMDARs currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age‐related synaptic impairments.

Mots clés

amyloid beta BACE1 β-secretase 1 BI β-secretase 1 inhibitor Ca2+ Calcium CTFs APP C-terminal fragments CTFα APP C-terminal fragment α CTFβ APP C-terminal fragment β cTKO triple conditional knockout DIV days in vitro EPSCs excitatory postsynaptic currents fEPSPs field excitatory postsynaptic potentials Ifen ifenprodil IPTG Isopropyl β-D-1-thiogalactopyranoside LTD long-term depression LTP long-term potentiation MAPT microtubule-associated protein tau NMDAR N-methyl-D-aspartate receptors NS1 nonsilencing sequence pGluN2B phosphorylated GluN2B PSD postsynaptic density PSD-95 Postsynaptic density protein 95 PSEN1 presenilin-1 PTB1-p PTB1 peptide PTB2-p PTB2 peptide PVDF polyvinylidene fluoride ROI region of interest RT room temperature sAPPα secreted APP α sAPPβ secreted APP β SEM standard error of the mean shAPP short-hairpin RNA against APP shCTR control short-hairpin RNA shRNA short-hairpin RNA τweighted weighted component amyloid beta BACE1 β-secretase 1 BI β-secretase 1 inhibitor Ca2+ Calcium CTFs APP C-terminal fragments CTFα APP C-terminal fragment α CTFβ APP C-terminal fragment β cTKO triple conditional knockout DIV days in vitro EPSCs excitatory postsynaptic currents fEPSPs field excitatory postsynaptic potentials Ifen ifenprodil IPTG Isopropyl β-D-1-thiogalactopyranoside LTD long-term depression LTP long-term potentiation MAPT microtubule-associated protein tau NMDAR N-methyl-D-aspartate receptors NS1 nonsilencing sequence pGluN2B phosphorylated GluN2B PSD postsynaptic density PSD-95 Postsynaptic density protein 95 PSEN1 presenilin-1 PTB1-p PTB1 peptide PTB2-p PTB2 peptide PVDF polyvinylidene fluoride ROI region of interest RT room temperature sAPPα secreted APP α sAPPβ secreted APP β SEM standard error of the mean shAPP short-hairpin RNA against APP shCTR control short-hairpin RNA shRNA short-hairpin RNA τweighted
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hal-04275549 , version 1 (13-11-2023)

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Joana Rajão‐saraiva, Jade Dunot, Aurore Ribera, Mariana Temido-Ferreira, Joana E Coelho, et al.. Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein. Aging Cell, 2023, 22 (3), ⟨10.1111/acel.13778⟩. ⟨hal-04275549⟩
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