title: Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice.
abstract: Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD.
  
  
  
  Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function.
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Jose Henrique
authors.identifier: 0000-0002-6693-3255
authors.initials: JH
authors.lastname: Ledo
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Estefania P
authors.identifier: 0000-0002-3149-7270
authors.initials: EP
authors.lastname: Azevedo
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Danielle
authors.identifier: 0000-0002-9584-4411
authors.initials: D
authors.lastname: Beckman
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Felipe C
authors.identifier: 0000-0003-3028-3307
authors.initials: FC
authors.lastname: Ribeiro
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, and.
authors.forename: Luis E
authors.identifier: 0000-0002-0694-733X
authors.initials: LE
authors.lastname: Santos
authors.affiliation: Faculty of Medical Sciences, University of Campinas, Campinas, 13083-887 Brazil.
authors.forename: Daniela S
authors.identifier: 0000-0002-2217-0946
authors.initials: DS
authors.lastname: Razolli
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Grasielle C
authors.initials: GC
authors.lastname: Kincheski
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Helen M
authors.identifier: 0000-0001-6141-3245
authors.initials: HM
authors.lastname: Melo
authors.affiliation: Institute of Microbiology Prof. Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 Brazil.
authors.forename: Maria
authors.identifier: 0000-0002-3360-2740
authors.initials: M
authors.lastname: Bellio
authors.affiliation: Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, 30130-100 Brazil, and.
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Teixeira
authors.affiliation: Faculty of Medical Sciences, University of Campinas, Campinas, 13083-887 Brazil.
authors.forename: Licio A
authors.identifier: 0000-0002-4806-7218
authors.initials: LA
authors.lastname: Velloso
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Debora
authors.identifier: 0000-0001-7312-7115
authors.initials: D
authors.lastname: Foguel
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis.|Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L3N6 Canada.
authors.forename: Fernanda G
authors.identifier: 0000-0001-8358-0589
authors.initials: FG
authors.lastname: De Felice
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis, ferreira@bioqmed.ufrj.br.|Institute of Biophysics Carlos Chagas Filho, and.
authors.forename: Sergio T
authors.identifier: 0000-0001-7160-9866
authors.initials: ST
authors.lastname: Ferreira
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000276:immunology*; D003863:Depression / Q000209:etiology / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000276:immunology; D020239:Receptor Cross-Talk / Q000276:immunology*; D012701:Serotonin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016229:Amyloid beta-Peptides; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin
keywords: Alzheimer's; depression; inflammation; microglia; serotonin