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Microglial response to Alzheimer’s disease is differentially modulated by voluntary wheel running and enriched environments

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Abstract

Alzheimer’s disease (AD) is an untreatable neurodegenerative disease that deteriorates memory. Increased physical/cognitive activity reduces dementia risk by promoting neuronal and glial response. Although few studies have investigated microglial response in wild-type rodents following exposure to physical/cognitive stimulation, environmental-induced changes of microglia response to AD have been neglected. We investigated effects of running (RUN) and enriched (ENR) environments on numerical density (N v, #/mm3) and morphology of microglia in a triple transgenic (3×Tg-AD) mouse model of AD that closely mimics AD pathology in humans. We used immunohistochemical approach to characterise microglial domain by measuring their overall cell surface, volume and somata volume. 3×Tg-AD mice housed in standard control (STD) environment showed significant increase in microglial N v (11.7 %) in CA1 stratum lacunosum moleculare (S.Mol) of the hippocampus at 12 months compared to non-transgenic (non-Tg) animals. Exposure to combined RUN and ENR environments prevented an increase in microglial N v in 3×Tg-AD and reduced microglial numbers to non-Tg control levels. Interestingly, 3×Tg-AD mice housed solely in ENR environment displayed significant decrease in microglial N v in CA1 subfield (9.3 % decrease), stratum oriens (11.5 % decrease) and S.Mol (7.6 % decrease) of the hippocampus compared to 3×Tg-AD mice housed in STD environment. Morphological analysis revealed microglial hypertrophy due to pronounced increase in microglia surface, volume and somata volume (61, 78 and 41 %) in 3×Tg-AD mice housed in RUN (but not in ENR) compared to STD environment. These results indicate that exposure to RUN and ENR environments have differential effects on microglial density and activation-associated changes in microglial morphology.

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Acknowledgments

The present study was supported by Alzheimer’s Research Trust Programme Grant (ART/PG2004A/1) to JJR and AV. Grant Agency of the Czech Republic (GACR 309/09/1696 and GACR 304/11/0184) to JJR and (GACR 305/08/1381; GACR 305/08/1384) to AV. The Spanish Government, Plan Nacional de I + D + I 2008-2011 and ISCIII-Subdirección General de Evaluación y Fomento de la investigación (PI10/02738) to JJR and AV and the Government of the Basque Country grant (AE-2010-1-28; AEGV10/16) to JJR, and by the Welcome Trust.

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Authors and Affiliations

  1. IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

    J. J. Rodríguez & A. Verkhratsky

  2. Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, 48940, Leioa, Spain

    J. J. Rodríguez & A. Verkhratsky

  3. INSERM U1051, Institute for Neurosciences of Montpellier, 80, av Augustin, Fliche, 34091, Montpellier Cedex 05, France

    H. N. Noristani

  4. Faculty of Life Sciences, The University of Manchester, Manchester, UK

    A. Verkhratsky

  5. Department of Neuroscience, IKERBASQUE, The University of the Basque Country UPV/EHU, Technological Park, Bldg. 205, Floor-1, Laida Bidea, 48170, Zamudio, Vizkaia, Spain

    J. J. Rodríguez

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Rodríguez, J.J., Noristani, H.N. & Verkhratsky, A. Microglial response to Alzheimer’s disease is differentially modulated by voluntary wheel running and enriched environments. Brain Struct Funct 220, 941–953 (2015). https://doi.org/10.1007/s00429-013-0693-5

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