title: Amyloid β peptide directly impairs pineal gland melatonin synthesis and melatonin receptor signaling through the ERK pathway.
abstract: Melatonin is the hormone produced by the pineal gland known to regulate physiologic rhythms and to display immunomodulatory and neuroprotective properties. It has been reported that Alzheimer disease patients show impaired melatonin production and altered expression of the 2 G protein-coupled melatonin receptors (MTRs), MT₁ and MT₂, but the underlying mechanisms are not known. Here we evaluated whether this dysfunction of the melatonergic system is directly caused by amyloid β peptides (Aβ(1-40) and Aβ(1-42)). Aβ treatment of rat pineal glands elicited an inflammatory response within the gland, evidenced by the up-regulation of 52 inflammatory genes, and decreased the production of melatonin up to 75% compared to vehicle-treated glands. Blocking NF-κB activity prevented this effect. Exposure of HEK293 cells stably expressing recombinant MT₁ or MT₂ receptors to Aβ lead to a 40% reduction in [(125)I]iodomelatonin binding to MT₁. ERK1/2 activation triggered by MTRs, but not by the β₂-adrenergic receptor, was markedly impaired by Aβ in HEK293 transfected cells, as well as in primary rat endothelial cells expressing endogenous MTRs. Our data reveal the melatonergic system as a new target of Aβ, opening new perspectives to Alzheimer disease diagnosis and therapeutic intervention.
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Cecon
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Marçola
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pedro A C
authors.initials: PA
authors.lastname: Fernandes
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.affiliation: *Chronopharmacology Laboratory, Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and University Paris Descartes, Sorbonne Paris Cité, Paris, France rpmarkus@usp.br.
authors.forename: Regina P
authors.initials: RP
authors.lastname: Markus
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000096:biosynthesis*; D010446:Peptide Fragments / Q000494:pharmacology*; D010870:Pineal Gland / Q000187:drug effects* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D010446:Peptide Fragments; D044094:Receptors, Melatonin; C075222:amyloid beta-protein (1-42); D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin
keywords: Alzheimer disease; nuclear factor κB