Background: Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is thought to be involved in the early processes of Alzheimer's disease. Increasing evidence indicates that these degenerative changes are likely caused by the binding of soluble Aβ oligomers to excitatory synapses. To date, the exact mechanism(s) by which Aβ oligomers bind to synapses and cause degenerative synaptotoxicity remains elusive. Methods: A recent siRNA screen with murine N2A cells suggested that Aβ-derived diffusible ligands (ADDLs) bound to the AMPA receptor, a major class of glutamate receptor that mediates fast excitatory synaptic transmission, on the surface of neurons. Subsequent ex vivo studies with primary rat hippocampal neurons showed that ADDLs bound to dendritic spines containing AMPA receptor subunits. Results: The ADDL binding was shown to be dependent on the presence of surface AMPA receptor, as treatments inducing internalization of AMPA receptors markedly reduced ADDL binding. Using an optimized affinity pull-down method, we also showed that AMPA receptors were present in the receptor complex bound to ADDLs. These results suggested that the binding of ADDLs to the receptor complex required the normal conformation of the AMPA receptor. Interestingly, we also found that while acute ADDL treatment induced a significant loss of surface AMPA receptor subunits from hippocampal neurons, repeated and chronic applications caused a striking aggregation of the AMPA receptor sbunit2 (gluR2) on the surface of dendrites as well as severe synapse loss. Conclusions: These results show that AMPA receptors are among the key components on the synaptic surface that are adversely affected by Aβ oligomers and suggest that oligomer-induced changes to synaptic morphology and the AMPA receptor signaling pathway may underlay some of the cognitive deficits seen in patients with Alzheimer's disease.