Oligomers of Amyloid-beta and Tau impair synaptic plasticity and memory in an APP dependent fashion

Background – Extracellular oligomers of amyloid-beta (oAβ) and Tau (oTau) are likely to play a key role in Alzheimer’s disease (AD). They have been shown to enter neurons and lead to an impairment of synaptic plasticity and memory. Interestingly, we have recently demonstrated that the concurrent application of subtoxic doses of oAβ and oTau impairs memory and its electrophysiological surrogate long-term potentiation (LTP). These findings prompted us to hypothesize that oAβ and oTau share a common mechanism in their detrimental effect against memory and synaptic plasticity. Specifically, we have tested whether Amyloid Precursor Protein (APP) is a key protein involved in a common mechanism by which extracellular oAβ and oTau interfere with second messenger cascades relevant to memory formation. Methods – We have first performed far-WB and co-immunoprecipitation studies to investigate whether oTau binds APP. To establish whether oAβ and oTau act in an APP-dependent fashion, we used APP knock-out (APPKO) mice. In particular, we examined whether suppression of APP function blocks: i) the intraneuronal uptake of oAβ and oTau in primary hippocampal neuronal cultures; ii) spatial and associative memory, tested through the Radial Arm Water Maze and Fear Conditioning; and iii) LTP at CA3/CA1 hippocampal synapses. Results – We found that, similar to oAβ, oTau is able to bind APP. Moreover, WT neurons internalized much more Aβ and Tau than APP-KO cells, suggesting that the expression of APP is required for intra-neuronal uptake of the two proteins. Finally, the deleterious effect of extracellular oAβ and oTau depended upon the presence of endogenous APP, since oAβ and oTau did not impair memory and LTP in APP KO mice. Conclusions – Both oAβ and oTau need APP to impair synaptic plasticity and memory, thus suggesting that the two proteins act through a key molecular common target. Despite the prevailing hypothesis in the AD field is that Aβ triggers Tau pathology, our data suggest that extracellular oAβ and oTau act in parallel, both through APP. Thus, APP represents an interesting therapeutic target against AD and other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau.