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.
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.
Jimenez
Sebastian
S
Department Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
Baglietto-Vargas
David
D
Caballero
Cristina
C
Moreno-Gonzalez
Ines
I
Torres
Manuel
M
Sanchez-Varo
Raquel
R
Ruano
Diego
D
Vizuete
Marisa
M
Gutierrez
Antonia
A
Vitorica
Javier
J
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
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