title: Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic.
abstract: Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration) has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus of PS1xAPP model, from an alternative activation state with Abeta phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-alpha and related factors) at 18 months of age. This switch was coincident with high levels of soluble Abeta oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric Abeta42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-alpha induction whereas monomeric Abeta42 and soluble extract from 6- or 18-month-old control and 6-month-old PS1xAPP hippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of Abeta pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble Abeta oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.
authors.affiliation: Department Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jimenez
authors.forename: David
authors.initials: D
authors.lastname: Baglietto-Vargas
authors.forename: Cristina
authors.initials: C
authors.lastname: Caballero
authors.forename: Ines
authors.initials: I
authors.lastname: Moreno-Gonzalez
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Varo
authors.forename: Diego
authors.initials: D
authors.lastname: Ruano
authors.forename: Marisa
authors.initials: M
authors.lastname: Vizuete
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; D017252:CD3 Complex; D005904:Glial Fibrillary Acidic Protein; D037102:Lectins; D053764:Presenilin-1; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II