Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease

Taylor R. Jay, Anna M. Hirsch, Margaret L. Broihier, Crystal M. Miller, Lee E. Neilson, Richard M. Ransohoff, Bruce T. Lamb, Gary E. Landreth

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficientADmouse models. In this study, we unify these previous findings by demonstrating thatTREM2deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1–21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology.

Original languageEnglish (US)
Pages (from-to)637-647
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number3
DOIs
StatePublished - Jan 18 2017

Keywords

  • AD
  • Genetic risk factor
  • Inflammation
  • Microglia
  • Myeloid cell
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)

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    Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017). Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. Journal of Neuroscience, 37(3), 637-647. https://doi.org/10.1523/JNEUROSCI.2110-16.2016