The effect of microglial DMT1 inhibition on neuroinflammation in male and female mice

Abstract

AbstractBackgroundNeuroinflammation and microglial activation are critical components of Alzheimer’s Disease neuropathology as observed in patients and animal models. Microglia have multiple functions in addition to their inflammatory phenotype that can contribute to disease. Specifically, iron accumulates in AD‐associated brain regions, and we and others have shown enhanced iron load in activated microglia surrounding amyloid‐beta (Aβ) plaques. Furthermore, we and others have shown a distinct upregulation in the microglial iron importer, divalent metal transporter 1 (DMT1) in response to Aβ. Our aim is to further elucidate the role of microglial iron‐handling in age and AD‐associated inflammation.MethodWe measured DMT1 gene expression to assess changes in iron‐handling in response to age and inflammation. Microglia isolated from aged mice were treated with an inflammatory Aβ stimulus before measuring DMT1 expression and immunohistochemical markers of iron load. To determine the role of microglial DMT1 during inflammatory pathology in vivo, we targeted DMT1 expression utilizing a microglial‐specific tamoxifen‐inducible genetic mouse model in males and females. Transgenic mice were given intraperitoneal lipopolysaccharide (LPS) as a widely‐used model of neuroinflammation. We isolated microglia 24hr after LPS administration and measured DMT1 expression via qRT‐PCR for knockdown confirmation. Sickness behavior and markers of inflammatory state were also assessed.ResultMicroglia from 2‐year‐old aged mice display an augmented increase in Aβ‐induced DMT1 expression compared to young controls. Our in vivo studies also suggest a sex‐dependent increase in microglial DMT1 expression following systemic LPS. In our genetic mouse model, we obtained a 79% and 89% knockdown of microglial DMT1 gene expression in males and females, respectively. Male knockdown animals exhibited a trending decrease in Il‐1β expression in response to LPS, indicating an intimate link between pro‐inflammatory signaling and microglial iron‐handling.ConclusionThese studies link changes in microglial iron‐handling and the neuroinflammatory response. Additional in vivo work is further being analyzed to comprehensively determine the effects of DMT1 inhibition on the neuroinflammatory response. Considering the prominence of iron‐loaded microglia and chronic neuroinflammation in late‐stage AD, early intervention aimed at a specific aspect of microglial iron‐handling could be a target to decrease inflammation and AD‐related pathology.