Abstract. Synapse loss occurs early in Alzheimer’s disease (AD) and is considered the best pathological correlate of cognitive
decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton
remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model
overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPPswe-ind mice). We found that
EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial
memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels
was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline
in hAβPPswe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found
changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may
cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture
increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in
the hippocampus leading to cognitive impairment in a model of AD
