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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.
Journal of Alzheimer's Disease – IOS Press
Published: Jan 1, 2009
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