Improvement in behavioral and psychiatric SYMPTOMS (BPSD) in patients with moderate-to-severe Alzheimer's disease by current antidementia treatments

questions relate to the interaction of Abeta oligomers with cell surface receptors. Abeta oligomers bind to a variety of such receptors, but it is uncertain which of these interactions has the greatest pathogenic impact on cognitive functions. Because binding of Abeta oligomers to EphB2 or PrP has been reported to cause severe synaptic andcognitive deficits in mice, we compared the consequences of modulating either of these transmembrane molecules in the same line of human amyloid precursor protein (hAPP) transgenic mice using the same battery of tests. Methods: Because binding of Abeta oligomers to EphB2 causes EphB2 depletion, we used lentiviral vectors to increase neuronal expression of EphB2 in hAPP-J20 mice. Because binding of Abeta oligomers to PrP has been reported to mediate impairments of synaptic plasticity and cognitive functions, we crossed hAPP-J20 mice onto aPrP-deficient background. A variety of biochemical, behavioral, and electrophysiological methods was used to assess these mice at 4-8 months of age. Results: Reversing EphB2 depletion in the dentate gyrus of hAPP mice reversed their deficits in NMDA receptor dependent long-term potentiation (LTP) as well as their memory impairments. In contrast, geneticablation of PrP did not prevent LTP deficits or behavioral abnormalities in hAPP mice. PrP ablation also failed to prevent the premature mortality seen in these mice. Conclusions: These results support our hypothesis that EphB2 depletion plays a critical role in the pathogenesis of Abeta-induced synaptic deficitsand memory impairments and highlight the therapeutic potential of modulating EphB2. Experiments to further explore this potential are in progress. Our results provide no support for a critical role of PrP in Abeta-dependent neuronal dysfunction.