PRESYNAPTIC AMYLOID PRECURSOR PROTEIN IS NECESSARY FOR THE IMPAIRMENT OF SYNAPTIC FUNCTION AND MEMORY CAUSED BY EXTRACELLULAR AMYLOID‐ΒETA AND TAU OLIGOMERS

Abstract

AbstractBackgroundAmyloid precursor protein (APP) is a transmembrane protein expressed at the synapse throughout life. In absence of APP, extracellular Aß‐ and tau‐oligomers no longer impair memory and its synaptic surrogate, long‐term potentiation (LTP). Synapses include pre‐ and post‐synaptic compartments. However, the relative role of pre‐ vs. post‐synaptic APP at the CA3‐CA1 hippocampal synapse in the Aß‐ and tau‐oligomer‐induced damage of memory and LTP is not know.MethodWe used a combination of gene editing, electrophysiological, behavioral and biochemical techniques to investigate the contribution of the pre‐ and post‐synaptic APP in oligomer induced impairment of memory and LTP.ResultSpecific ablation of APP expression in the post‐synaptic neuron did not alter the negative effects of Aß and tau oligomers on LTP and memory. In contrast, APP‐KO in the presynaptic neuron mimicked and occluded the negative effects of Aß and tau oligomers on LTP and memory, suggesting that presynaptic APP mediates the synapto‐toxic effect of Aß and tau. Further investigation demonstrated that pre‐synaptic APP deletion (but not post‐synaptic) mimicked and occluded the Aß and tau oligomer induced reduction of neurotransmitter vesicle availability during tetanic stimulation and increase of refilling rate after depletion of the readily‐releasable pool. Moreover, the increase in refilling rate after deletion of presynaptic APP was dependent upon intracellular calcium. Indeed, intracellular calcium homeostasis was affected both in basal conditions and after activity in full APP‐KO mice, likely due to decrease in the levels of inositol 1,4,5‐trisphosphate receptor, ryanodine receptor and the calcium pump, SERCA3.ConclusionThese data support the view that Aß and tau oligomers affect synaptic function and memory through pre‐synaptic APP.