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Articles, Neurobiology of Disease

Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers

Huixin Xu, Eilrayna Gelyana, Molly Rajsombath, Ting Yang, Shaomin Li and Dennis Selkoe
Journal of Neuroscience 31 August 2016, 36 (35) 9041-9056; DOI: https://doi.org/10.1523/JNEUROSCI.1023-16.2016
Huixin Xu
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Eilrayna Gelyana
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Molly Rajsombath
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Ting Yang
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Shaomin Li
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Dennis Selkoe
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Abstract

Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble Aβ oligomers (oAβ) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oAβ-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFα) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oAβ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oAβ, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.

SIGNIFICANCE STATEMENT Environmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human Aβ oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.

  • Alzheimer's disease
  • brain inflammation
  • environmental enrichment
  • microglia
  • oligomeric amyloid beta
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The Journal of Neuroscience: 36 (35)
Journal of Neuroscience
Vol. 36, Issue 35
31 Aug 2016
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Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers
Huixin Xu, Eilrayna Gelyana, Molly Rajsombath, Ting Yang, Shaomin Li, Dennis Selkoe
Journal of Neuroscience 31 August 2016, 36 (35) 9041-9056; DOI: 10.1523/JNEUROSCI.1023-16.2016

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Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers
Huixin Xu, Eilrayna Gelyana, Molly Rajsombath, Ting Yang, Shaomin Li, Dennis Selkoe
Journal of Neuroscience 31 August 2016, 36 (35) 9041-9056; DOI: 10.1523/JNEUROSCI.1023-16.2016
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Keywords

  • Alzheimer's disease
  • brain inflammation
  • environmental enrichment
  • microglia
  • oligomeric amyloid beta

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