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      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

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          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 Aβ phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-α 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-α 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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          5 November 2008
          : 28
          : 45
          : 11650-11661
          Affiliations
          [1] 1Department Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain,
          [2] 2Department Biologia Celular, Genetica y Fisiologia. Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain,
          [3] 3Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) 41013 Sevilla, Spain,
          [4] 4Instituto de Biomedicina de Sevilla (IBiS)–Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
          Author notes
          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. vitorica@ 123456us.es

          *S.J., D.B.-V., and C.C. contributed equally to this work.

          Article
          PMC6671312 PMC6671312 6671312 3418114
          10.1523/JNEUROSCI.3024-08.2008
          6671312
          18987201
          b2885ec4-f731-4252-952c-daca8b183f21
          Copyright © 2008 Society for Neuroscience 0270-6474/08/2811650-12$15.00/0
          History
          : 30 June 2008
          : 18 September 2008
          : 27 September 2008
          Categories
          Articles
          Neurobiology of Disease
          Custom metadata
          true
          neurobiology-of-disease

          hippocampus,oligomers,hippocampus Aβ plaques,neuroinflammation,transgenic model,Alzheimer

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