NMDA-Receptor Activation but Not Ion Flux Is Required for Amyloid-Beta Induced Synaptic Depression

Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer’s disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

[1]  R. Malinow,et al.  Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression , 2013, Proceedings of the National Academy of Sciences.

[2]  N. Leclerc,et al.  Interaction of Endogenous Tau Protein with Synaptic Proteins Is Regulated by N-Methyl-d-aspartate Receptor-dependent Tau Phosphorylation* , 2012, The Journal of Biological Chemistry.

[3]  L. Schneider,et al.  Lack of evidence for the efficacy of memantine in mild Alzheimer disease. , 2011, Archives of neurology.

[4]  Julie A. Harris,et al.  Reversing EphB2 depletion rescues cognitive functions in Alzheimer model , 2011, Nature.

[5]  R. Anwyl,et al.  GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo , 2009, Proceedings of the National Academy of Sciences.

[6]  J. Qi,et al.  Amyloid β‐protein fragments 25–35 and 31–35 potentiate long‐term depression in hippocampal CA1 region of rats in vivo , 2009, Synapse.

[7]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[8]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[9]  W. Klein,et al.  Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease , 2007, The Journal of Neuroscience.

[10]  R. Malinow,et al.  AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss , 2006, Neuron.

[11]  Roberto Malinow,et al.  Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1 , 2006, Neuron.

[12]  Jon W. Johnson,et al.  Mechanism of action of memantine. , 2006, Current opinion in pharmacology.

[13]  R. Anwyl,et al.  Long-Term Depression of NMDA Receptor-Mediated Synaptic Transmission Is Dependent on Activation of Metabotropic Glutamate Receptors and Is Altered to Long-Term Potentiation by Low Intracellular Calcium Buffering , 2006, The Journal of Neuroscience.

[14]  P. Keller,et al.  Globular amyloid β‐peptide1−42 oligomer − a homogenous and stable neuropathological protein in Alzheimer's disease , 2005 .

[15]  Q. Tang,et al.  A Novel Ca2+-Independent Signaling Pathway to Extracellular Signal-Regulated Protein Kinase by Coactivation of NMDA Receptors and Metabotropic Glutamate Receptor 5 in Neurons , 2004, The Journal of Neuroscience.

[16]  M. Bear,et al.  Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1 , 2004, The Journal of Neuroscience.

[17]  W. K. Cullen,et al.  Soluble Arctic amyloid β protein inhibits hippocampal long‐term potentiation in vivo , 2004, The European journal of neuroscience.

[18]  D. Teplow,et al.  Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease , 2004, Neurobiology of Aging.

[19]  D. Selkoe,et al.  Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. , 2003, Annual review of pharmacology and toxicology.

[20]  W. Ju,et al.  Glycine binding primes NMDA receptor internalization , 2003, Nature.

[21]  Roberto Malinow,et al.  Subunit-Specific NMDA Receptor Trafficking to Synapses , 2002, Neuron.

[22]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[23]  Rand Askalan,et al.  Tyrosine Phosphatase STEP Is a Tonic Brake on Induction of Long-Term Potentiation , 2002, Neuron.

[24]  G. Westbrook,et al.  A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux , 2001, Nature Neuroscience.

[25]  R. Anwyl,et al.  Use-Dependent Effects of Amyloidogenic Fragments of β-Amyloid Precursor Protein on Synaptic Plasticity in Rat Hippocampus In Vivo , 2001, The Journal of Neuroscience.

[26]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[27]  P. A. Peterson,et al.  β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity , 2000, Journal of Biological Chemistry.

[28]  R. Nicoll,et al.  Two Distinct Forms of Long-Term Depression Coexist in CA1 Hippocampal Pyramidal Cells , 1997, Neuron.

[29]  N Butters,et al.  Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. , 1994, Archives of neurology.

[30]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[31]  W. Klein,et al.  Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  P. Greengard,et al.  Regulation of NMDA receptor trafficking by amyloid-beta. , 2005, Nature neuroscience.

[33]  P. Keller,et al.  Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease. , 2005, Journal of neurochemistry.

[34]  P. Hutzler,et al.  Neurobiology of Disease Soluble ␤-amyloid 1– 40 Induces Nmda-dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses , 2022 .