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Cognitive dysfunction in Alzheimer’s disease (AD) is associated with the accumulation of amyloid-β (Aβ) oligomers in the brain, which are thought to impair neurotransmission by interfering with the function of neuronal NMDA-type glutamate receptors. Although AD has been associated with low levels of EphB2 – a receptor tyrosine kinase that regulates NMDA receptors – whether EphB2 depletion contributes to cognitive dysfunction has been unclear. Using the human amyloid precursor (hAPP) transgenic mouse model of AD, Cissé and colleagues now show that Aβ oligomers cause depletion of EphB2 levels and, in turn, decrease synaptic strength and cognitive defects. Aβ oligomers were found to interact directly with EphB2 and trigger its degradation. Knockdown of EphB2 in nontransgenic mice caused neuronal deficits similar to those in the hAPP mice, whereas rescue of EphB2 levels in hAPP mice by using viral vectors corrected cognitive deficits. These results clarify the role of EphB2 in learning and memory, and suggest that it might be a therapeutic target for AD.
Cissé M., Halabisky B., Harris J., Devidze N., Dubal D.B., Sun B., Orr A., Lotz G., Kim D.H., Hamto P., et al. ( 2010). Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature [Epub ahead of print] 10.1038/nature09635 [PMC free article] [PubMed] [Cross Ref]