title: Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss.
abstract: Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-D-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca(2+) entry, however, also Ca(2+)-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca(2+) chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca(2+) flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca(2+) flux- and G protein-independent mechanisms.
authors.affiliation: 1] Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland [2] Graduate Program of the Zurich Neuroscience Center, University of Zurich, Schlieren, Switzerland.
authors.forename: J H
authors.initials: JH
authors.lastname: Birnbaum
authors.affiliation: 1] Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland [2] Systems and Cell Biology of Neurodegeneration, University of Zurich, Schlieren, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bali
authors.affiliation: 1] Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland [2] Systems and Cell Biology of Neurodegeneration, University of Zurich, Schlieren, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Rajendran
authors.affiliation: Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland.
authors.forename: R M
authors.initials: RM
authors.lastname: Nitsch
authors.affiliation: Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Tackenberg
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D049229:Dendritic Spines / Q000473:pathology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D004533:Egtazic Acid; D016291:Dizocilpine Maleate; C056639:2-amino-5-phosphopentanoic acid; D037342:Pertussis Toxin; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D014633:Valine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D008559:Memantine