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The Journal of Neuroscience, November 5, 2008, 28(45):11650-11661; doi:10.1523/JNEUROSCI.3024-08.2008

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Neurobiology of Disease
Inflammatory Response in the Hippocampus of PS1_M146L/APP_751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic

Sebastian Jimenez,^1,3,4 * David Baglietto-Vargas,^2,3 * Cristina Caballero,^1,3,4 * Ines Moreno-Gonzalez,^2,3 Manuel Torres,^1,3,4 Raquel Sanchez-Varo,^2,3 Diego Ruano,^1,3,4 Marisa Vizuete,^1,3,4 Antonia Gutierrez,^2,3 and Javier Vitorica^1,3,4

¹Department Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain, ²Department Biologia Celular, Genetica y Fisiologia. Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain, ³Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) 41013 Sevilla, Spain, ⁴Instituto de Biomedicina de Sevilla (IBiS)–Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain

Correspondence should be addressed to Javier Vitorica, Department Bioquímica, Bromatologia, Toxicologia y Medicina Legal, Facultad de Farmacia. Universidad de Sevilla, C/ Prof. Garcia Gonzalez 2, 41012 Sevilla, Spain. Email: vitorica{at}us.es

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 Aβ phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF- and related factors) at 18 months of age. This switch was coincident with high levels of soluble Aβ oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric Aβ42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF- induction whereas monomeric Aβ42 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 Aβ 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 Aβ oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.

Key words: Alzheimer; transgenic model; neuroinflammation; hippocampus Aβ plaques; oligomers; hippocampus

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Received June 30, 2008; revised Sept. 18, 2008; accepted Sept. 27, 2008.

Correspondence should be addressed to Javier Vitorica, Department Bioquímica, Bromatologia, Toxicologia y Medicina Legal, Facultad de Farmacia. Universidad de Sevilla, C/ Prof. Garcia Gonzalez 2, 41012 Sevilla, Spain. Email: vitorica{at}us.es

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