Effect of A beta Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons

Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-beta oligomers (A beta os) and propagates from neuron to neuron. Here, we investigated the mechanism by which A beta os affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild -type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of A beta os on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of A beta os reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that A beta os/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced A beta os. Intracellular A beta os participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against A beta os. Furthermore, we provide evidence that following APP processing, extracellular release of Aflos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for A beta os in AD, while intracellular A beta os alter synaptic function, extracellular A beta os promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.