November 24, 2020

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

The patterns of A{beta}-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{beta} 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 {gamma}-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by A{beta}. Taken together, these results demonstrate that APP/A{beta}-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment.

 bioRxiv Subject Collection: Neuroscience

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