Abstract
Synaptic dysfunction occurs early in the progression of Alzheimer’s disease (AD) and correlates with memory decline. There is emerging evidence that deregulation of Erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinases (RTK) signaling contributes to the aberrant synaptic functions associated with neurodegeneration. The Eph receptor A4 is highly expressed in human adult hippocampal brain tissue and was previously linked to cognitive impairment in a transgenic mouse model for AD. Whether EphA4 levels are altered in AD brain remains elusive. Therefore we investigated the protein levels and localization of EphA4 in human hippocampus derived from AD (n = 29) as well as non-demented control cases (n = 19).The total EphA4 protein levels were not changed in AD patients compared to control cases. However, immunohistochemical localization of EphA4 revealed an altered distribution in AD compared to control hippocampus. EphA4 immunoreactivity was observed in plaque-like structures in AD cases. Double-labelling with phosphorylated tau and amyloid beta indicates that EphA4 co-localizes with neuritic plaques in AD. This altered distribution pattern was observed at early stages (Braak stage II) and correlates with the hallmarks of AD pathology suggesting a reduced availability of EphA4 that is likely to contribute to synaptic dysfunction that occurs early in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0079-9) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has an increasing effect on our ageing population
In the present study we report on the involvement of EphA4 in human AD pathology
Synaptic failure correlates with cognitive decline and is observed in patients with mild cognitive impairment (MCI) and incipient AD [3]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has an increasing effect on our ageing population. There is emerging evidence that the erythropoietin-producing hepatocellular (Eph) receptors and their ligands, the so-called. Activation of EphA4 upon binding to its glia-derived ligand ephrin A3 was found to induce spine retraction and to trigger the reduction of dendritic spines and synaptic proteins, whereas inhibiting those interactions led to distorted spine shape and organization in the murine hippocampus. These findings suggest an essential role for EphA4 in the elimination of excitatory synapses [18,19,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
