Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice

Erica M. Weekman, Tiffany L. Sudduth, Erin L. Abner, Gabriel J. Popa, Michael D. Mendenhall, Holly M. Brothers, Kaitlyn Braun, Abigail Greenstein, Donna M. Wilcock

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Background: The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer's disease, yet the impact of these phenotypes on amyloid-beta (Aβ) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces Aβ, but long-term studies have not been performed that track the neuroinflammatory phenotype. Methods: Wild-type and APP/PS1 transgenic mice aged 3 to 4 months received a bilateral intracranial injection of adeno-associated viral (AAV) vectors expressing IFNγ or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFNγ protein levels and biochemical levels of Aβ. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and Aβ levels were assessed with immunohistochemistry. Results: AAV expressing IFNγ induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in Aβ at 6 months. Microglial staining was increased at 6 months and astrocyte staining was decreased at 4 and 6 months in mice receiving AAV expressing IFNγ. Conclusions: Expression of IFNγ through AAV successfully induced an M1 phenotype at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that a mixed phenotype, or enhanced expression of M2a and M2c markers, could contribute to increasing amyloid burden and disease progression.

Original languageEnglish
Article number127
JournalJournal of Neuroinflammation
Volume11
Issue number1
DOIs
StatePublished - Jul 25 2014

Bibliographical note

Publisher Copyright:
© 2014 Weekman et al.; licensee BioMed Central Ltd.

Keywords

  • Alzheimer's disease
  • Beta-amyloid
  • Inflammation
  • Microglia

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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