Rusty Microglia: Trainers of Innate Immunity in Alzheimer's Disease

Abstract

Alzheimer's disease, the most common form of dementia, is marked by progressive cognitive and functional impairment believed to reflect synaptic and neuronal loss. Recent preclinical data suggests that lipopolysaccharide (LPS)-activated microglia may contribute to the elimination of viable neurons and synapses by promoting a neurotoxic astrocytic phenotype, defined as A1. The innate immune cells, including microglia and astrocytes, can either facilitate or inhibit neuroinflammation in response to peripherally applied inflammatory stimuli, such as LPS. Depending on previous antigen encounters, these cells can assume activated (trained) or silenced (tolerized) phenotypes, augmenting or lowering inflammation. Iron, reactive oxygen species (ROS), and LPS, the cell wall component of gram-negative bacteria, are microglial activators, but only the latter can trigger immune tolerization. In Alzheimer's disease, tolerization may be impaired as elevated LPS levels, reported in this condition, fail to lower neuroinflammation. Iron is closely linked to immunity as it plays a key role in immune cells proliferation and maturation, but it is also indispensable to pathogens and malignancies which compete for its capture. Danger signals, including LPS, induce intracellular iron sequestration in innate immune cells to withhold it from pathogens. However, excess cytosolic iron increases the risk of inflammasomes' activation, microglial training and neuroinflammation. Moreover, it was suggested that free iron can awaken the dormant central nervous system (CNS) LPS-shedding microbes, engendering prolonged neuroinflammation that may override immune tolerization, triggering autoimmunity. In this review, we focus on iron-related innate immune pathology in Alzheimer's disease and discuss potential immunotherapeutic agents for microglial de-escalation along with possible delivery vehicles for these compounds.

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Central nervous system. Impaired iron homeostasis in the CNS is coupled with neuroinflammation, oxidative stress, neurodegenerative disease pathology, and cognitive decline (100)(101)(102)(103). Accordingly, iron must be tightly regulated on a cell-to-cell basis to ensure normal homeostatic function.…”

“…Accordingly, iron must be tightly regulated on a cell-to-cell basis to ensure normal homeostatic function. Microglia, the resident Mɸs of the CNS, play an integral role in regulating brain iron levels (102,(104)(105)(106)(107)(108)(109). Microglia express iron transport and storage proteins, including DMT1, TfR, ferritin, Fpn, and hepcidin, and acquire both holo-Tf and NTBI (104,107).…”

Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory

“…On the other hand, maladapted trained immunity can be detrimental to human health. Chronic inflammatory conditions including neuropsychiatric conditions have been implicated with maladapted changes in trained immunity [2,9]. It should also be noted that induction of trained immunity appears to be associated with doses of PAMP, perhaps DAMP in humans; depending on the dose and the kinds of PAMP/DAMP, tolerance can be induced, instead of trained immunity [2].…”

“…This type of innate immune memory (tolerance) is thought to be important in maintaining brain homeostasis, and impaired tolerance of innate immunity has been suspected in chronic neurodegenerative conditions such as Alzheimer's disease [9]. Aging is associated with an increased load of gram-negative bacteria in the GI tract and mouth mucosa, resulting in an increase in endotoxin levels in the blood and the brain [62].…”

“…Innate immunity has also been known to shape adaptive immunity through multiple mechanisms such as affecting actions of APCs, thereby indirectly modifying adaptive immune responses [7]. However, recent exciting research revealed that innate immunity can have its own memory, following an immune stimulus, and this depends on time, amount, and the kinds of stimuli through metabolic and epigenetic changes [3,9]. More importantly, the stimuli that evoke innate immune memory are not restricted to microbes; nonpathogenic challenges such as stress and obesity are also found to cause innate immune memory [3,10].…”