Effect of Aβ Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons
Marta Rolland, Rebecca Powell, Muriel R. Jacquier‐Sarlin, Sylvie Boisseau, Robin Reynaud-Dulaurier, José Martínez Hernández, Louise André, Eve Borel, Alain Buisson, Fabien Lanté
Abstract
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-b oligomers (Abos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Abos 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 Abos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Abos 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 Abos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Abos. Intracellular Abos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Abos. Furthermore, we provide evidence that following APP processing, extracellular release of Abos 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 Abos in AD, while intracellular Abos alter synaptic function, extracellular Abos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.