title: The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation.
abstract: Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) 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 Aβ 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 Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ 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 Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia.
authors.affiliation: Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Peters
authors.affiliation: Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Chile.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Sepúlveda
authors.affiliation: Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Chile.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Fernández-Pérez
authors.affiliation: Laboratory of Biomedical Sciences, Marquette University, Milwaukee, WI, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Peoples
authors.affiliation: Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Chile.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Aguayo
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate
keywords: Alzheimer’s disease; NMDA receptor; amyloid-beta; glutamate; glycine receptor; hippocampal neurons; membrane damage; membrane pore