Arginase 1+ microglia reduce Ab plaque deposition during IL 1b dependent neuroinflammation
BackgroundNeuroinflammation has long been considered a driver of Alzheimer's disease progression. However, experiments developed to explore the interaction between neuroinflammation and Alzheimer's disease (AD) pathology showed a surprising reduction in amyloid beta (Ab) plaque deposition. We sought to understand this unexpected outcome by examining microglia phenotypes during chronic neuroinflammation.MethodsUsing an adeno associated virus vector carrying hIL 1b cDNA, inflammation was induced in one hippocampus of 8 month old amyloid precursor protein (APP)/PS1 mice for 4 weeks, while the other hemisphere received control injections. Bone marrow chimeras and staining analysis were used to identify the origins and types of immune cells present during sustained inflammation. Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS) immunoreactivity were used as markers of alternatively activated and classically activated cells, respectively, and changes in cellular uptake of Ab by Arg1+ or iNOS+ microglia was demonstrated by confocal microscopy. To determine if an anti inflammatory phenotype was present during neuroinflammation, RNA was extracted on flow sorted microglia and rt PCR was performed. Interleukin 4 injection was used to induce alternatively activated cells, whereas a minipump and intrahippocampal cannula was used to deliver an interleukin (IL) 4Ra antibody to block the induction of Arg1+ cells in the setting of sustained IL 1b expression.ResultsWe observed a robust upregulation of centrally derived Arg1+ microglia present only in the inflamed hemisphere. Furthermore, in the inflamed hemisphere, greater numbers of Arg1+ microglia contained Ab when compared to iNOS+ microglia. RNA isolated from flow sorted microglia from the inflamed hemisphere demonstrated elevation of mRNA species consistent with alternative activation as well as neuroprotective genes such as BDNF and IGF1. To explore if Arg1+ microglia mediated plaque reduction, we induced Arg1+ microglia with IL 4 and observed significant plaque clearance. Moreover, when we reduced Arg1+ microglia induction in the context of neuroinflammation using an anti IL 4Ra antibody delivered via intrahippocampal cannula, we observed a clear correlation between numbers of Arg1+ microglia and plaque reduction.ConclusionsTogether, these findings suggest that Arg1+ microglia are involved in Ab plaque reduction during sustained, IL 1b dependent neuroinflammation, opening up possible new avenues for immunomodulatory therapy of AD.
Journal of Neuroinflammation