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-beta peptide (A beta) 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 beta 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 beta on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of A beta to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and A beta. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because A beta was now unable to cause membrane perforation, suggesting a complex relationship between A beta and NMDARs. Because previous studies have recognized that A beta 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 beta actions in hippocampal neurons. These results could explain the lack of correlation between brain A beta burden and clinically observed dementia.