Aβ and Tau oligomers affect synaptic plasticity and memory in an APP-dependent fashion

Amyloid-β (Aβ) and Tau protein exert a physiological role at synapses, but their abnormal increase has been implicated in the pathogenesis of Alzheimer’s disease (AD) and other disorders characterized by memory loss. We have previously demonstrated that extracellular Aβ and Tau oligomers (oAβ and oTau) applied alone or concurrently at subtoxic doses, are capable of impairing memory and its cellular surrogate, long-term potentiation (LTP). These effects are likely to be mediated by internalization into neurons. Considering that the two proteins share several biochemical and functional features, here we hypothesized that oAβ and oTau act through a common mechanism mediated by Amyloid Precursor Protein (APP) to induce the detrimental effect on LTP and memory. We have used APP knock-out (APP-KO) mice to investigate whether suppression of APP function blocks: i) the intra-neuronal uptake of oAβ and oTau in primary hippocampal cultures; ii) memory, tested by Radial Arm Water Maze and Fear Conditioning; iii) LTP. We have first shown that, as for oAβ, APP is able to bind oTau. Moreover, the expression of APP is needed for intra-neuronal uptake of oAβ and oTau. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon the presence of APP since APP-KO animals were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, our data suggest that extracellular oAβ and oTau act in parallel, both through APP.