Loss of IBA1-Expression in brains from individuals with obesity and hepatic dysfunction

Abstract

Microglia, the brain’s resident immune cells, exhibit constitutive expression of the ionized calcium binding adaptor molecule 1 (IBA1), a cytoplasmic protein with actin and calcium-binding functions involved in membrane ruffling. Microglia are long-lived cells that exhibit a senescent morphology (dystrophy) with aging, which may be indicative of cell dysfunction. It has been reported that dystrophy of IBA1-positive microglia is exacerbated in obese humans. Our own preliminary studies of microglia in the medial temporal lobe of obese subjects have revealed another microglial abnormality, which is the loss of IBA1 immunoreactivity that can create large areas in the brain seemingly devoid of all microglial cells. Here, we systematically compared microglial appearance in human hippocampi derived from obese individuals compared to controls (nobese = 33, nnon-obese = 30). In both groups, we found areas that were negative for IBA1, but contained P2YR12 and glutathione-peroxidase 1 (GPX)-positive microglia. The number and extent of IBA1-negative regions was increased in obese cases. Since some cases of non-obese individuals also exhibited loss of IBA-1 immunoreactivity, we searched for possible confounders and found that hepatic dysfunction strongly impacts the distribution of microglial cells: By computational analysis of scanned IBA1-stained sections, we detected increased Mean Empty Space distances (p = 0.016) and IBA1-negative areas (p = 0.090) which were independent from the cause of liver dysfunction, but also from aging. Thus, we report on a novel type of microglia pathological change, i.e. localized loss of IBA1 that is linked, at least in part, to obesity and hepatic dysfunction.