Virus-induced brain pathology and the neuroinflammation-inflammation continuum: the neurochemists view

Abstract

Fascinatingly, an abundance of recent studies has subscribed to the importance of cytotoxic immune mechanisms that appear to increase the risk/trigger for many progressive neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis, and multiple sclerosis. Events associated with the neuroinflammatory cascades, such as ageing, immunologic dysfunction, and eventually disruption of the blood-brain barrier and the "cytokine storm", appear to be orchestrated mainly through the activation of microglial cells and communication with the neurons. The inflammatory processes prompt cellular protein dyshomeostasis. Parkinson's and Alzheimer's disease share a common feature marked by characteristic pathological hallmarks of abnormal neuronal protein accumulation. These Lewy bodies contain misfolded α-synuclein aggregates in PD or in the case of AD, they are Aβ deposits and tau-containing neurofibrillary tangles. Subsequently, these abnormal protein aggregates further elicit neurotoxic processes and events which contribute to the onset of neurodegeneration and to its progression including aggravation of neuroinflammation. However, there is a caveat for exclusively linking neuroinflammation with neurodegeneration, since it's highly unlikely that immune dysregulation is the only factor that contributes to the manifestation of many of these neurodegenerative disorders. It is unquestionably a complex interaction with other factors such as genetics, age, and environment. This endorses the "multiple hit hypothesis". Consequently, if the host has a genetic susceptibility coupled to an age-related weakened immune system, this makes them more susceptible to the virus/bacteria-related infection. This may trigger the onset of chronic cytotoxic neuroinflammatory processes leading to protein dyshomeostasis and accumulation, and finally, these events lead to neuronal destruction. Here, we differentiate "neuroinflammation" and "inflammation" with regard to the involvement of the blood-brain barrier, which seems to be intact in the case of neuroinflammation but defect in the case of inflammation. There is a neuroinflammation-inflammation continuum with regard to virus-induced brain affection. Therefore, we propose a staging of this process, which might be further developed by adding blood- and CSF parameters, their stage-dependent composition and stage-dependent severeness grade. If so, this might be suitable to optimise therapeutic strategies to fight brain neuroinflammation in its beginning and avoid inflammation at all.

Keywords: Neurodegeneration; Alzheimer’s disease; Cytotoxicity; Immunology; Inflammation; Microglia and neuroinflammation; Parkinson’s disease; Viruses.

Fig. 1

Sequence of events that may be related to viral-related infection coupled with other risk factors in Parkinson’s disease. Viruses (HIN1, H5N1, FLAVI, HEP.C, HIV, etc) gain entry through the olfactory or/and gastric avenues, inciting neuroinflammation in the respiratory and gastrointestinal tract respectively. This leads to the release of proinflammatory cytokines and chemokines, which can disrupt the integrity of the blood-brain barrier (BBB) by producing fenestrations on its endothelial cells. Thus, making it “leaky” and allowing the passage of pathogens/toxins to the brain. On gaining entry to the brain, these cytokines can activate microglia (M1 cells) via toll-like receptors (2,4, and 9), which generates further production of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α, etc.) and onset neuroinflammation in the brain. Also, chronic neuroinflammation has been implicated in familial PD. Neuroinflammation may contribute to the dysregulation of protein clearance pathways, resulting in the build-up of misfolded α-synuclein, mitochondrial malfunction, and cytotoxic reactions resp. oxidative/nitrative stress by the generation of reactive free radicals. Eventually, these neurotoxic processes coupled with other risk factors (age, genetic predisposition, and environmental factors) ultimately destroy the dopaminergic nigral neurons in PD. Key: BBB-blood brain barrier; PD-Parkinson’s disease; SN substantia nigra; NM neuromelanin; iNOS-inducible nitric oxide/FAK pathway;TLR-Toll-like receptors; IL-Interleukin;TNF- α tumor necrosis factor; α-syn-alpha synuclein; HSV-1 herpes simplex virus -1;Hep.C hepatitis C virus; Flavi-flaviviruses; H1N1 Influenza A virus; H5N1 avian influenza; and HIV human immunodeficiency virus

Fig. 2

Consequences of α-synuclein aggregation in PD. Accumulates of misfolded α-synuclein can provoke an array of consequences that exacerbate the burden of neuronal destruction. Including; activation of microglia, further disruption of protein metabolism, and activation of NLRP3 inflammasome (there also may be involvement of genetic components). Subsequently, these processes marshal in a “cytokine storm” or excess release of cytokines, thereby ushering in a state of chronic neuroinflammation and neuronal death

Fig. 3

Neuroinflammatory-mediated degenerative mechanisms that may be operating in the pathogenesis of Alzheimer’s disease, NF-κB regulates the enhanced expression of pro-inflammatory DAM genes (Cd44, Nampt, and Cst2). An increase in the expression of these genes can prompt the activation of DAM causing the generation of inflammatory mediators (for example, PG E2, IL-6) and inflammation. Neuroinflammation can elicit cytotoxic processes such as oxidative stress, and disturbance of protein clearance pathways, thereby resulting in a build-up of Aβ deposits and tau neurofibrillary tangles. The presence of these pathological markers herald’s neurodegeneration characteristics of the disease. Key: NF-κB nuclear factor kappa B; ROS reactive oxygen species; DAM disease-associated microglia; PG E2 prostaglandin E2; IL-6-Interleukin 6; NOX2 NADPH OXIDASE 2; NFT-tau neurofibrillary tangles containing tau and Aβ amyloid beta

Fig. 4

Apolipoprotein E e4 (ApoE e4) function in Alzheimer’s disease, Carriers of APOE e4 gene bestow the operation of many cellular toxic actions. These events are exacerbated in the presence of particular viral infections (HSV-1, influenza virus, and varicella-zoster virus). These pathways share a common microglial-mediated neuroinflammatory route that eventually contributes to the appearance of pathological markers and neurodegeneration typical of the disease. Key: HSV-1 herpes simplex virus -1

Fig. 5

Signal molecules and proteins associated with chronic inflammation and neuroinflammation resulting in neurodegeneration. Molecules released from inflammatory processes can activate Toll-receptors, which in turn stimulate signal molecules (such as JAK/STAT or MAPK or NF-κB) and their pathways. In addition, pro-inflammatory M1 microglia phenotype can also stimulate these signal pathways. The polarization of the M1 microglial is supported by, NF-κB, STAT1, and STAT3, whereas the appearance of anti-inflammatory M2 microglial is favored by IL-4, IL-13, IL-33, STAT 6 and Neuropeptide Y. Consequently, chronic inflammation and neuroinflammation generate reactive oxygen species that induce oxidative stress. Other factors may also initiate the production of reactive oxygen species including dopamine, elevated iron, neuromelanin, nitric oxide, depleted glutathione, endo/exotoxin, genetic predisposition, and mitochondrial dysfunction. Eventually, oxidative stress, accumulation of protein aggregates, and other cytotoxic processes lead to the destruction of cells. Key: ROS reactive oxygen species; JAK/STAT Janus kinase and signal transducer of activation; MAPK mitogen-activated protein kinase; NF-κB nuclear factor kappa B; IL interleukin; DA dopamine; NM neuromelanin; NO nitric oxide; GSH reduced glutathione