Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons

ABSTRACT The patterns of Aβ-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, A(plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with γ-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by Aβ. Taken together, these results demonstrate that APP/Aβ-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment.