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Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein

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, and interfering with this mechanism normalized the aberrant currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments. In brief Rajão-Saraiva et al. identified the APP full-length protein as a regulator of glutamatergic transmission in immature synapses, by controlling GluN2B synaptic content and mediated currents during postnatal development. Upon aging, the APP amyloidogenic derived C-terminal fragments, rather than APP full length, contribute to aberrant GluN2B-NMDAR currents. Our work highlights the importance of keeping APP processing under tight control, to ensure the normal functioning of glutamatergic synapses, being particularly relevant to understand age-related synaptic impairments and AD.