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 AMPA-receptor (AMPAR) imaging on mice and rat neurons to demonstrate that GluA3 expression in neurons lacking GluA3 is sufficient to re-sensitize 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 towards endo-lysosomal 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 is a critical early step in the cascade of events through which Aβ accumulation causes a loss of synapses.Significance statement Early cognitive symptoms in Alzheimer's disease are considered to be driven by dysfunctional synapses. Studies in animal models for Alzheimer's disease have demonstrated that the preservation of synapses alleviates cognitive symptoms. However, a clinically viable approach to preserve synapses requires a mechanistic understanding of how synaptic function is perturbed. Our study reveals that synapse impairments in Alzheimer models require the synaptic removal and subsequent lysosomal degradation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that contain subunit GluA3. Preventing this aberrant trafficking of GluA3 leads to the preservation of synapses. This study identifies that the presence of GluA3 determines whether synapses are vulnerable to Alzheimer pathology, thereby deepening our understanding of how synapses are affected in Alzheimer's disease.