Abstract
Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer’ s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD.
Highlights
The brain is among the most metabolically active organs in the body and accounts for at least 20% of the body’s energy consumption
The metal is directly implicated in the disease known as neurodegeneration with brain iron accumulation (NBIA), and, in addition to other trace elements implicated in neurodegeneration, including copper [8], manganese [9], and zinc [10], increasing evidence support iron’s role in several other sporadic or genetic neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) [11,12,13,14]
These resident macrophages are largely involved in immune responses and, depending on the stimuli, they can adopt a range of pro- or anti-inflammatory states to help maintain the integrity of the neural environment [17,18,19]
Summary
The brain is among the most metabolically active organs in the body and accounts for at least 20% of the body’s energy consumption. Our understanding of the role of iron in normal brain function has improved tremendously over the last decade, with much attention directed towards deciphering the cellular and molecular cues that guide brain iron transport and metabolism. Microglia make up 5 to 12% of the population of cells found in mouse brain and about 0.5 to 16% of those in the human brain [15,16] These resident macrophages are largely involved in immune responses and, depending on the stimuli, they can adopt a range of pro- or anti-inflammatory states to help maintain the integrity of the neural environment [17,18,19]. This review will examine the influence of brain iron on microglial metabolism and corresponding inflammatory responses under normal and neurodegenerative conditions, with a particular focus on AD
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