Alzheimer’s disease (AD) is one most common dementia. Although there is currently no effective treatment, the reversal of amyloid beta (Aβ)-induced synaptic deficits is believed to be a promising therapeutic approach. Our laboratory previously demonstrated that the activation of EphA4, an erythropoietin-producing hepatocellular (Eph) receptor family member, can reduce the surface levels of AMPA receptors and cause dendritic spine loss; moreover, blockade of EphA4 signaling reverses impaired synaptic plasticity in AD mouse models. In order to investigate the regulatory mechanism by which EphA4 inhibition reverses synaptic impairment in AD, we generated ephA4^−/− APP/PS1 triple-transgenic mice. Immunohistochemical analysis of amyloid plaque deposition in the brain of the triple-transgenic...[ Read more ]

Alzheimer’s disease (AD) is one most common dementia. Although there is currently no effective treatment, the reversal of amyloid beta (Aβ)-induced synaptic deficits is believed to be a promising therapeutic approach. Our laboratory previously demonstrated that the activation of EphA4, an erythropoietin-producing hepatocellular (Eph) receptor family member, can reduce the surface levels of AMPA receptors and cause dendritic spine loss; moreover, blockade of EphA4 signaling reverses impaired synaptic plasticity in AD mouse models. In order to investigate the regulatory mechanism by which EphA4 inhibition reverses synaptic impairment in AD, we generated ephA4^−/− APP/PS1 triple-transgenic mice. Immunohistochemical analysis of amyloid plaque deposition in the brain of the triple-transgenic mice showed no difference in the number of plaques deposited in ephA4^+/− APP/PS1 or ephA4^−/− APP/PS1 mice compared with APP/PS1 mice at 9 or 12 months of age. On the other hand, long-term potentiation (LTP) in hippocampal CA1 region sections at the same ages indicates synaptic plasticity impairment in ephA4^−/− APP/PS1 mice. Reported study showed the LTP impairment was found in ephA4^−/− mice. These results collectively demonstrate critical roles of EphA4 during development; its global depletion causes LTP impairment ahead of AD pathogenesis at later stage and conceals EphA4 specific function during AD progression. Furthermore, as the expression of β-secretase 1 (BACE1), the key enzyme for APP processing, was reduced in ephA4^−/− APP/PS1 mouse brains, future studies should determine if EphA4 is involved in APP processing. In order to determine how EphA4 regulates AD pathogenesis, conditionally knockout of EphA4 in AD mouse models may be a better system for the study.