Amyloid beta peptide directly impairs pineal gland melatonin synthesis and melatonin receptor signaling through the ERK pathway

Author(s)

Cecon, Erika ^{[1, 2, 3, 4]} ; Chen, Min ^{[1, 2, 3]} ; Marcola, Marina ^[4] ; Fernandes, Pedro A. C. ^[4] ; Jockers, Ralf ^{[1, 2, 3]} ; Markus, Regina P. ^[4]

Affiliation

^[1] INSERM, Inst Cochin, U1016, Paris - France

^[2] CNRS, Unite Mixte Rech 8104, Paris - France

^[3] Univ Paris 05, Sorbonne Paris Cite, Paris - France

^[4] Univ Sao Paulo, Inst Biosci, Chronopharmacol Lab, Sao Paulo - Brazil

• Document type: Journal article
• Source: FASEB JOURNAL; v. 29, n. 6, p. 2566-2582, JUN 2015.
• Web of Science Citations: 25

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 beta peptides (A beta(1-40) and A beta(1-42)). A beta 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-kappa B activity prevented this effect. Exposure of HEK293 cells stably expressing recombinant MT1 or MT2 receptors to A beta lead to a 40% reduction in {[}I-125] iodomelatonin binding to MT1. ERK1/2 activation triggered by MTRs, but not by the beta(2)-adrenergic receptor, was markedly impaired by A beta 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 A beta, opening new perspectives to Alzheimer disease diagnosis and therapeutic intervention. (AU)

• FAPESP's process: 09/17923-9 - Pineal gland as a target for B-amyloid peptide
• Grantee: Erika Cecon
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/01304-8 - Effect of melatonin on the subpopulations of cultured endothilial cells
• Grantee: Marina Marçola Pereira de Freitas
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 07/07871-6 - Imune-pineal Axis: injury shifts melatonin production from endocrine to paracrine
• Grantee: Regina Pekelmann Markus
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/13691-1 - Immune-pineal axis: time-niology integrated to surveillance and defense
• Grantee: Regina Pekelmann Markus
• Support Opportunities: Research Projects - Thematic Grants