Neuroinflammation leads to N/A, Neurodegeneration

It is well accepted that chronic neuroinflammation is involved in the pathogenesis of neurodegenerative diseases (McNaull et al., 2010; Tansey and Goldberg, 2009; Thundyil and Lim, 2015 ). Chronic neuroinflammation can cause secondary damage (Kraft and Harry, 2011). The mechanisms by which neuroinflammation (i.e. activated microglia and astrocytes) can kill neurons and induce/exacerbate the neurodegenerative process has been suggested to include the release of nitric oxide that causes inhibition of neuronal respiration, ROS and RNS production, and rapid glutamate release resulting in excitotoxic death of neurons (Brown & Bal-Price, 2003; Kraft & Harry, 2011; Taetzsch & Block, 2013). Glial reactivity is also associated with excessive production and release of pro-inflammatory cytokines that not only affect neurons, but also have detrimental feedback effects on microglia (Heneka et al., 2014). For example, sustained exposure to bacterial lipopolysaccharide (LPS) or to other pro-inflammatory mediators was shown to restrict microglial phagocytosis of misfiled and aggregated proteins (Sheng et al., 2003). Systemic immune challenge during pregnancy leading to microglial activation caused increased deposition of amyloid plaques and tau hyperphosphorylation in aged mice (Krstic et al., 2012, 2013), suggesting that neuroinflammation is involved in the amyloid plaques and neurofibrillary tangles formation. There is further evidence that the formation of neurofibrillary tangles is caused by microglial cell-driven neuroinflammation, since LPS-induced systemic inflammation increased tau pathology (Kitazawa et al., 2005).

Sars-CoV-2 specific evidence:

Studies on post-mortem cases indicate that lymphocytes and monocytes infiltrate in brain vessel walls, exacerbating the neuronal degeneration and demyelination process (Wu et al., 2020)

The aberrant immune response characterized by a surge in cytokine levels (e.g., IL-6) derived by SARS-CoV-2 accelerates the process of neurodegeneration that may contribute to the development of neurodegenerative diseases (Debnath et al. 2020).

SARS-CoV-2 can infect human brain organoids resulting in unique metabolic changes and the death of infected and neighbouring neurons. This phenotype is accompanied by impaired synaptogenesis (Song et al., 2020) (Mesci et al, 2020).

Moreover, it is hypothesized that an autoimmune reaction mediated by the cross-reaction between viral particles and myelin basic protein may provide the driving force for neural demyelination, as part of the neurodegenerative process. This hypothesis is supported by the fact that the genome of other coronaviruses like CoV-OC43 and CoV-229E, as well as their antibodies, has been isolated from the CNS of Multiple Sclerosis (MS) patients, and coronavirus-like particles have been found in perivascular cuffs of human MS brain (Montalvan et al. 2020). In fact, the virus might lie dormant in astrocytes and oligodendrocytes and trigger the autoimmunity mediated by molecular mimicry (Mohammadi et al., 2020).

Neurons are the target cells undergoing degeneration during infection, in part due to apoptosis (de Assis et al. 2020). Intracerebral inoculation with CoV-OC43 in susceptible mice led to an acute encephalitis, with neuronal cell death by necrosis and apoptosis (Jacomy H, et al. 2006).

SARS-CoV infection causes neuronal death (even in the absence of encephalitis) in mice transgenic for human ACE2. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centres in the medulla. The absence of the host cell receptor prevents severe murine brain disease (Netland J, et al. 2008).

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

There are few studies where markers of neuroinflammation are measured simultaneously with markers of cell death and neurodegeneration. In addition, neuroinflammation is a complex KE, since the neurodegenerative consequences depend on the microglial phenotype, which has been measured only in very recent studies. An attempt to link KE_up to KE_down quantitatively is provided below.

The hypotheisis of developmental origin of Pb-induced neurodegeneration was tested and observed in Zebra fish by Lee and Freeman (2014).