Effects of Low Amyloid-β (Aβ) Concentration on Aβ1-42 Oligomers Binding and GluN2B Membrane Expression

Numerous studies have shown that amyloid-beta (A beta) modulate intracellular metabolic cascades and an intracellular Ca2+ homeostasis and a cell surface NMDA receptor expression alteration in Alzheimer's disease (AD). However most of these findings have been obtained by using non-physiological A beta concentrations. The present study deals with the effect of low A beta concentrations on cellular homeostasis. We used nerve growth factor-differentiated PC12 cells and murine cortical neurons sequentially treated with low chronic monomeric or small oligomeric A beta concentrations and high acute oligomeric A beta concentrations to bring out a priming effect of chronic treatment on subsequently high A beta concentrations-elicited cellular response. Both cell types indeed displayed an enhanced capacity to bind oligomeric A beta after monomeric or small oligomeric A beta application. Furthermore, the results show that monomeric A beta 1-42 application to the cells induces an increase of the Ca2+-response and of the membrane expression of the extrasynaptic subunit of the NMDA receptor GluN2B in PC12 cells, while the opposite effects were observed in cultured neurons. This suggests a sequential interaction of A beta with the cellular plasma membrane involving monomers or small A beta oligomers which would facilitate the binding of the deleterious high molecular A beta oligomers. This mechanism would explain the slow progression of AD in the human nervous system and the deep gradient of neuronal death observed around the amyloid plaques in the nervous tissue.