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

Joana Rajão-Saraiva1, Jade Dunot2, Aurore Ribera2

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Aging Cell
|January 27, 2023
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The amyloid precursor protein (APP) regulates N-methyl-D-aspartate receptors (NMDARs) differently across life stages. APP supports synaptic maturation in infants, while its fragments impair receptor function in aging brains.

Keywords:
AICDAPPAlzheimer's diseaseFe65GluN2BNMDA receptoragingexcitatory synapsehippocampuspostnatal development

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Synaptic Plasticity

Background:

  • N-methyl-D-aspartate receptors (NMDARs), particularly those with GluN2B subunits, are crucial for hippocampal synaptic function.
  • The amyloid precursor protein (APP) is implicated in NMDAR regulation, but its precise role remains unclear.

Purpose of the Study:

  • To investigate the dual mechanisms by which APP influences GluN2B-NMDAR function throughout different life stages.
  • To elucidate the impact of APP and its fragments on synaptic plasticity and age-related synaptic impairments.

Main Methods:

  • Patch-clamp electrophysiology
  • Molecular biology techniques
  • Analysis of APP processing in aging mouse and human brain tissues

Main Results:

  • APP is abundant at the postsynapse in infant mice, regulating GluN2B-NMDARs and synaptic currents.
  • Amyloidogenic C-terminal fragments of APP, not full-length APP, cause aberrant GluN2B-NMDAR currents in aging.
  • Increased APP processing and altered GluN2B-NMDAR currents were observed in aging mice and humans.
  • Modulating APP intracellular domain stability or production normalized GluN2B-NMDAR currents.

Conclusions:

  • APP plays a dual role in NMDAR function: essential for synaptic maturation in development and a contributor to age-related synaptic dysfunction via its fragments.
  • Targeting APP processing may offer therapeutic strategies for age-related synaptic impairments.