Fig. 4

EBV infection and neuroinflammatory alterations: implications in neurotransmission and copper metabolism. A Exosomes with EBV dUTPases and EBERs from EBV-infected cells can reach the blood–brain barrier and contact endothelial cells causing activation of TLR2 receptors by dUTPases. The blood–brain barrier’s endothelial cells are activated and release proinflammatory cytokines that disrupt the blood–brain barrier’s integrity. Both EBV-infected cells crossing the blood–brain barrier and exosomes with viral genetic material can activate microglia through TLR3 receptors that detect the presence of EBERs. Activated microglia release proinflammatory cytokines IL-1β and TNF-α, which increase the expression and activity of the serotonin transporter SERT in astrocytes, causing an increase in serotonin (5-HT) reuptake and a decrease in its extracellular levels. Oligodendrocytes are particularly susceptible to inflammation. Overexposure to cytokines such as TNF-α can damage these cells, potentially leading to apoptosis and demyelination. Both increased proinflammatory cytokines and increased oxidative and nitrosative stress (ROS/RNS) from activation of microglia via TLR3 could lead to increased IDO activity in microglia, resulting in reduced tryptophan (TRP) levels, increased kynurenine catabolites and decreased 5-HT synthesis. Quinolinic acid (QUIN) stimulates glutamate (GLU) release by activating the NMDA glutamate receptor in the presynaptic neuron. On the other hand, in astrocytes it decreases the expression of glutamate transporters and increases their release, thus increasing extracellular glutamate levels. Thus, quinolinic acid can increase glutamate levels in the brain and decrease brain cells' ability to eliminate excess glutamate. Moreover, quinolinic acid has neurotoxic properties by binding to the neurons' NMDA receptor, followed by sustained calcium (Ca²⁺) influx leading to increased oxidative and nitrosative stress. This increase in nitrosative and oxidative stress leads to the activation of PARP-1 polymerase to prevent DNA damage. But continuous overactivation of PARP-1 leads to depletion of intracellular reserves of nicotinamide adenine dinucleotide (NAD) and ATP, with the consequent alteration in energy production and mitochondrial function. The binding of glutamate to extrasynaptic NMDA receptors can lead to a reduction in the levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), leading to a decrease in synaptic plasticity and increased vulnerability to excitotoxicity. The decrease in 5-HT levels decreases the activation of 5-HT1A receptors allowing more glutamate to be released, as the activation of 5-HT1A receptors decreases the release of glutamate in presynaptic neurons. In addition, the activation of 5-HT1A receptors in the postsynaptic neuron inhibits the activation of NMDA receptors, so a decrease in extracellular 5-HT prevents the activation of 5-HT1A receptors allowing overexcitation of NMDA receptors by glutamate and quinolinic acid. B To the right, the same process occurs, but with alterations in dopaminergic neurons. The decrease in extracellular 5-HT levels due to increased 5-HT reuptake decreases the activation of 5-HT1A receptors in neurons allowing more dopamine (DA) to be released, as the activation of 5-HT1A receptors decreases the release of dopamine in presynaptic neurons. Additionally, the activation of 5-HT1A receptors in the postsynaptic neuron inhibits the activation of NMDA receptors, so a decrease in extracellular 5-HT prevents the activation of 5-HT1A receptors allowing overexcitation of NMDA receptors by quinolinic acid and excess glutamate released by glutaminergic neurons. In turn, the decrease in 5-HT levels decreases the activation of astrocytes’ 5-HT1A receptors, leading to less release of metallothioneins (MT) to the extracellular space. Metallothioneins are especially important to protect dopaminergic neurons from excess dopamine quinones. Consequently, a decrease in the availability of copper in these cells due to a decrease in metallothionein production and copper absorption in the intestine would lead to a decrease in dopamine breakdown via MAO, as this enzyme’s activity depends on copper. If MAO enzymes cannot efficiently break down dopamine, more dopamine may accumulate in the cytosol of neurons and undergo autoxidation. Then, in conditions of copper deficiency in dopaminergic neurons, there could be a greater propensity to form dopamine quinones and ROS due to the autoxidation of accumulated dopamine, causing mitochondrial dysfunction. In addition, the activation of microglia in response to inflammatory stimuli would increase copper uptake from the synaptic space by microglia and disrupt neuronal copper reuptake. This can decrease the amount of copper available for neurons, disrupting their ability to regulate NMDA receptor activity and leading to overactivation of NMDA receptors. Increased copper in microglia can reduce its ability to phagocytose unwanted proteins. This could lead to an accumulation of amyloid-beta (Aβ) protein released by neurons. These Aβ deposits also have a high affinity for copper, so a greater increase in Aβ in these areas would cause larger amounts of copper to deposit out of reach of neurons and even form Aβ amyloid plaques