Model Senescent Microglia Induce Disease Related Changes in Alpha-synuclein Expression and Activity

Dafina Angelova, David Brown

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Aging is the most prominent risk factor for most neurodegenerative diseases. However, incorporating aging-related changes into models of neurodegeneration rarely occurs. One of the significant changes that occurs in the brain as we age is the shift in phenotype of the resident microglia population to one less able to respond to deleterious changes in the brain. These microglia are termed dystrophic microglia. In order to better model neurodegenerative diseases, we have developed a method to convert microglia into a senescent phenotype in vitro. Mouse microglia grown in high iron concentrations showed many characteristics of dystrophic microglia including, increased iron storage, increased expression of proteins, such as ferritin and the potassium channel, Kv1.3, increased reactive oxygen species production and cytokine release. We have applied this new model to the study of α-synuclein, a protein that is closely associated with a number of neurodegenerative diseases. We have shown that conditioned medium from our model dystrophic microglia increases α-synuclein transcription and expression via tumor necrosis factor alpha (TNFα) and mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The conditioned medium also decreases the formation of α-synuclein tetramers, associated ferrireductase activity, and increases aggregates of α-synuclein. The results suggest that we have developed an interesting new model of aged microglia and that factors, including TNFα released from dystrophic microglia could have a significant influence on the pathogenesis of α-synuclein related diseases
Original languageEnglish
Article number67
Pages (from-to)1-25
Number of pages25
JournalBiomolecules
Volume8
Issue number3
Early online date1 Aug 2018
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • Aging
  • Cytokines
  • Iron
  • Microglia
  • Synuclein
  • Tetramer
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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