Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein
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
Aβ
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
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers produits par l'(les) auteur(s) |
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Licence |
Domaine public
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