Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity

Abstract

Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34-97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 +/- 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain.

Iron, Aging, and Neurodegeneration

“…Additionally, an outward rectifier K + channel called Kv1.3 has been found to increase expression in dystrophic microglia in aged mouse brains [146]. Dystrophic microglia become more prevalent with human aging and have been found to increase in a variety of diseases including AD [147] and Huntington's disease [148]. There is also evidence that the chronic inflammation that accompanies neurodegeneration leads to local increases in microglia with high iron and ferritin content, possibly due to iron scavenging [149].…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…Microglia density in the CNS tissue increases with age (Poliani et al 2015), but a subset of these cells in humans, highly expressing ferritin, shows signs of dystrophy or senescence, characterized by a reduction and beading of cell processes (Lopes et al 2008). Microglia senescence is particularly prominent in the brain of aging patients with progressive MS and is associated with a prominent loss of microglia and macrophages in inactive lesions in comparison to the normal-appearing white matter (Hametner et al 2013;Zrzavy et al 2017).…”

Protective Effects of Curcumin on Manganese-Induced BV-2 Microglial Cell Death

“…27) Although there are limited reports on the effects of Mninduced toxicity on glial cells, some studies suggested that self-produced ROS can stimulate degradation of ferritin in microglia and subsequent microglial cell death. 29,30) However, little is known about the molecular mechanisms responsible for Mn toxicity in microglia.…”