Amyloid-β(1-42) peptide induces rapid NMDA receptor-dependent alterations at glutamatergic synapses in the entorhinal cortex

The hippocampus and entorhinal cortex (EC) accumulate amyloid beta peptides (A beta) that promote neuropathology in Alzheimer's disease, but the early effects of A beta on excitatory synaptic transmission in the EC have not been well characterized. To assess the acute effects of A beta(1-42) on glutamatergic synapses, acute brain slices from wildtype rats were exposed to A beta(1-42) or control solution for 3 hours, and tissue was analyzed using protein immunoblotting and quantitative PCR. Presynaptically, A beta(1-42) induced marked reductions in synaptophysin, synapsin-2a mRNA, and mGluR3 mRNA, and increased both VGluT2 protein and Ca2+-activated channel KCa2.2 mRNA levels. Postsynaptically, A beta(1-42) reduced PSD95 and GluN2B protein, and also downregulated GluN2B and GluN2A mRNA, without affecting scaffolding elements SAP97 and PICK1. mGluR5 mRNA was strongly increased, while mGluR1 mRNA was unaffected. Blocking either GluN2A- or GluN2B-containing NMDA receptors did not significantly prevent synaptic changes induced by A beta(1-42), but combined blockade did prevent synaptic alterations. These findings demonstrate that A beta(1-42) rapidly disrupts glutamatergic transmission in the EC through mechanisms involving concurrent activation of GluN2A- and GluN2B-containing NMDA receptors. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The study found that Aβ(1-42) can rapidly disrupt glutamatergic transmission in the entorhinal cortex, primarily by affecting molecular levels presynaptically and postsynaptically, and involving concurrent activation of GluN2A- and GluN2B-containing NMDA receptors.