Reelin signaling antagonizes beta-amyloid at the synapse.
Abnormal processing of the amyloid precursor protein (APP) and beta-amyloid (Abeta) plaque accumulation are defining features of Alzheimer disease (AD), a genetically complex neurodegenerative disease that is characterized by progressive synapse loss and neuronal cell death. Abeta induces synaptic dysfunction in part by altering the endocytosis and trafficking of AMPA and NMDA receptors. Reelin is a neuromodulator that increases glutamatergic neurotransmission by signaling through the postsynaptic ApoE receptors Apoer2 and Vldlr and thereby potently enhances synaptic plasticity. Here we show that Reelin can prevent the suppression of long-term potentiation and NMDA receptors, which is induced by levels of Abeta comparable to those present in an AD-afflicted brain. This reversal is dependent upon the activation of Src family tyrosine kinases. At high concentrations of Abeta peptides, Reelin can no longer overcome the Abeta induced functional suppression and this coincides with a complete blockade of the Reelin-dependent phosphorylation of NR2 subunits. We propose a model in which Abeta, Reelin, and ApoE receptors modulate neurotransmission and thus synaptic stability as opposing regulators of synaptic gain control.
Durakoglugil
Murat S
MS
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chen
Ying
Y
White
Charles L
CL
Kavalali
Ege T
ET
Herz
Joachim
J
D000544:Alzheimer Disease / Q000209:etiology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D001921:Brain / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000494:pharmacology / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D000091042:Reelin Protein; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases