Growing evidence has shown that inflammation could be a hallmark contributor to AD development and exacerbation. Pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 are upregulated in brains of individuals with AD, which leads to an accumulation of Aβ plaque aggregates and tau hyperphosphorylation resulting in neuronal loss. Inflammation in the brain is mediated by astrocytes and microglia. Microglia has multiple functions, but one important role established is being the scavenger cells of the brain responding to disuse damage and apoptosis. Neuronal injury from amyloid plaques is increased by the production of neurotoxic Aβ in response to cytokines and inflammatory stimuli. Deposition of Aβ in the brain results in neuroinflammation by triggering microglia, which is stated to be a major source of pro-inflammatory cytokines in AD. After microglia phagocytize the amyloid, they decrease the clearance process of amyloid over time, since amyloid is difficult to proteolyze. Microglia then becomes compromised and less efficient in breaking down amyloid plaques. They release more pro-inflammatory cytokines, which may further exacerbate AD progression.
Mechanisms proposed for microglia degeneration include TREM2, CX3CR1, GABA, and other inflammatory cytokine mediators. TREM2 is an innate immune receptor expressed on the cell surface of microglia that causes macrophages to activate phagocytosis causing the release of reactive oxygen species. A study done on mice has shown that TREM2 alters phagocytosis and lipid metabolism exacerbating AD. Numerous studies demonstrate that the CX3CL1/CX3CR1 receptor ligands, another transcription factor and chemokine, can dose-dependently suppress the death of neurons by activating microglia and decrease levels of nitric oxide, IL-6, and TNF-α after stimulation of lipopolysaccharide. However, postmortem studies in AD patients showed decreased levels of CX3CL1 when compared with age-matched controls. In addition, the study done on mice stated that genetic deletion of CX3CR1 changes the inflammatory process, resulting in higher Aβ phagocytosis in microglia. CX3CL1/CX3CL1 affects not only microglia, but tau hyperphosphorylation as well. AD transgenic mice with a CX3CR1 deletion led to increased tau phosphorylation, accumulation, microglial activation, and an increased deficit in hippocampal learning, exacerbating AD.
Microglia also releases pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1β. These cytokines play a central role in the regulation and beginning phases of inflammation, allowing leukocytes and immune cells to migrate to sites by increasing vascular and endothelial adhesion molecules. IL-1β, synthesized by activated microglia and astrocytes, regulates the formation of amyloid-β protein precursor from glial cells, which is a precursor to amyloid plaques. One study showed that IL-1β is overexpressed by microglia and astrocytes at Aβ plaques, and they are present in AD brains and animal models of AD when compared to age controls. This study provides evidence that overexpression of IL-1β exacerbates tau phosphorylation and neurofibrillary tangles by activation of different kinases.
Astrocytes, also considered as a supportive cell, play an integral role in AD. Astrocytes are involved in cell signaling, synaptic remodeling, and management of oxidative stress. When they become reactive, astrocytes express inflammatory mediators. High levels of extracellular S100B, which is released from astrocytes via IL-1β due to pro-inflammatory mediators and other triggers, can act as a cytokine and have been increased in clinical conditions that include brain trauma, ischemia and neurodegenerative, and inflammatory and psychiatric diseases. Researchers at Northwestern University concluded the protein S100B, a protein that induces neurite proliferation, is overexpressed in AD brains. These effects can increase brain inflammation and escalate amyloid plaques from amyloid-β protein precursor. In addition, exposure of cultured astrocytes to Aβ significantly upregulates IL-1β, TNF-α, IL-6, and NO production, therefore intensifying inflammation and progression of AD [19].
Increasing research shows that oligodendrocyte, the myelin forming cells in the central nervous system, can contribute to oxidative stress. One proposed mechanism for oxidative stress previously shown in rat models, is that oligodendrocytes have a greater decreased glutathione content than any other cell in the brain and an increased iron content, which make them more vulnerable to oxidative stress and damage [19]. Oligodendrocytes can lead to increased complement in AD brains, exacerbating inflammation. Aβ is also potentially toxic to oligodendrocytes. According to a study done in mice, oligodendrocytes exposed with Aβ oxidative stress can lead to cell death, resulting in demyelination. This demyelination decreases the neuron action potential time and increases cognitive impairment in AD. This evidence suggests that neurons in the nervous system play a role in increasing inflammation and stress, thereby increasing the progression of AD.
It is vital to have a balance between oxidants and antioxidants. When unbalanced, the overproduction of reactive oxygen species (ROS) or lack of antioxidants leads to oxidative stress. Free radicals are generated from both endogenous and exogenous sources, such as inflammation, ischemia, cancer, aging, environmental pollutants, cigarette smoke, alcohol, and heavy metals, such as mercury, and iron. Oxidants are generated in our bodies from cellular by-products of metabolism or external factors such as ionizing radiation.
However, in AD, the activity of antioxidant enzymes is altered, which leads to the free buildup of oxidative damage. These oxidants can be detrimental to our cellular structures that provide the scaffolding and integrity in AD brains through DNA oxidation products, hydroxyl radical pairing with DNA bases, and lipid peroxidation. Oxidant levels that are too high can result in cell damage. Oxidative species is a characteristic of AD brains, especially in the pathology of senile plaques. Before the presence of Aβ pathology and clinical symptoms, there is evidence that the production of ROS increases due to mitochondrial damage. Antioxidants decrease free-radical-mediated damage in neuronal cells through detoxification, and if the balance between antioxidants/oxidants are unbalanced unfavorably, there can be detrimental effects, especially in the AD brain.
**content of this article is from the National Library of Medicine