Synapse loss occurs early in Alzheimer's disease (AD) and is considered thebest pathological correlate of cognitive decline. Ephrins and Eph receptorsare involved in regulation of excitatory neurotransmission and play a rolein cytoskeleton remodeling. We asked whether alterations in Eph receptorscould underlie cognitive impairment in an AD mouse model overexpressinghuman amyloid-β protein precursor (hAβPP) with familialmutations (hAβPP swe-ind mice). We found that EphA4 and EphB2receptors were reduced in the hippocampus before the development of impairedobject recognition and spatial memory. Similar results were obtained inanother line of transgenic AβPP mice, Tg2576. A reduction in Ephreceptor levels was also found in postmortem hippocampal tissue frompatients with incipient AD. At the time of onset of memory decline inhAβPP swe-ind mice, no change in surface expression of AMPA orNMDA receptor subunits was apparent, but we found changes in Eph-receptordownstream signaling, in particular a decrease in membrane-associatedphosho-cofilin levels that may cause cytoskeletal changes and disruptedsynaptic activity. Consistent with this finding, Eph receptor activation incell culture increased phosho-cofilin levels. The results suggest thatalterations in Eph receptors may play a role in synaptic dysfunction in thehippocampus leading to cognitive impairment in a model of AD.