Amyloid-β-Driven Synaptic Deficits Are Mediated by Synaptic Removal of GluA3-Containing AMPA Receptors.

The detrimental effects of oligomeric amyloid-β (Aβ) on synapses are considered the leading cause for cognitive deficits in Alzheimer's disease. However, through which mechanism Aβ oligomers impair synaptic structure and function remains unknown. Here, we used electrophysiology and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) imaging on mouse and rat neurons to demonstrate that GluA3 expression in neurons lacking GluA3 is sufficient to resensitize their synapses to the damaging effects of Aβ, indicating that GluA3-containing AMPARs at synapses are necessary and sufficient for Aβ to induce synaptic deficits. We found that Aβ oligomers trigger the endocytosis of GluA3 and promote its translocation toward endolysosomal compartments for degradation. Mechanistically, these Aβ-driven effects critically depend on the PDZ-binding motif of GluA3. A single point mutation in the GluA3 PDZ-binding motif prevented Aβ-driven effects and rendered synapses fully resistant to the effects of Aβ. Correspondingly, proteomics on synaptosome fractions from APP/PS1-transgenic mice revealed a selective reduction of GluA3 at an early age. These findings support a model where the endocytosis and lysosomal degradation of GluA3-containing AMPARs are a critical early step in the cascade of events through which Aβ accumulation causes a loss of synapses.