title: Activated microglia mediate synapse loss and short-term memory deficits in a mouse model of transthyretin-related oculoleptomeningeal amyloidosis.
abstract: Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.
authors.affiliation: Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil.
authors.forename: E P
authors.initials: EP
authors.lastname: Azevedo
authors.forename: J H
authors.initials: JH
authors.lastname: Ledo
authors.forename: G
authors.initials: G
authors.lastname: Barbosa
authors.forename: M
authors.initials: M
authors.lastname: Sobrinho
authors.forename: L
authors.initials: L
authors.lastname: Diniz
authors.forename: A C C
authors.initials: AC
authors.lastname: Fonseca
authors.forename: F
authors.initials: F
authors.lastname: Gomes
authors.forename: L
authors.initials: L
authors.lastname: Romão
authors.forename: F R S
authors.initials: FR
authors.lastname: Lima
authors.forename: F L
authors.initials: FL
authors.lastname: Palhano
authors.forename: S T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: D
authors.initials: D
authors.lastname: Foguel
mesh_terms: D000682:Amyloid; D028227:Amyloid Neuropathies, Familial / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004705:Endocytosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008569:Memory Disorders / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008911:Minocycline / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011228:Prealbumin / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000682:Amyloid; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D011228:Prealbumin; D014409:Tumor Necrosis Factor-alpha; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D008911:Minocycline