The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid- peptide (A) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with A affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by A on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of A to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and A. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because A was now unable to cause membrane perforation, suggesting a complex relationship between A and NMDARs. Because previous studies have recognized that A oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on A actions in hippocampal neurons. These results could explain the lack of correlation between brain A burden and clinically observed dementia.