N/A, Neurodegeneration leads to Neuroinflammation

According to its definition, neurodegeneration includes the death of neurons. Therefore, the KER describing the link between cell death and neuroinflammation is also applicable to this KER. However in neurodegenerative diseases and in Alzheimer's disease in particular, neurodegneration is associated with accumulation of modified/aggregated proteins (insoluble amyloid; hyperphosphorylated tau), which are recognised as potential triggers of neuroinflammation:

Proteinopathies associated with neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD) may be sensed as damage associated molecular patterns (DAMPs) and thus activate microglia within the CNS. In animal neurodegeneration models and post-mortem brain samples from  patients suffering from neurodegenerative disorders often revealed the presence of activated microglia and the accumulation of inflammatory mediators at the lesion sites, which suggests a continuous crosstalk between the brain immune system and the injured neurons during neurodegeneration. Microglial are typically activated acutely in response to an initial triggering insult, but their continued presence in large numbers around the lesion areas may actually promote neuronal death despite the absence of the initial triggering insult. Inflammatory factors being released by dying neurons and/or actively secreted from the activated microglia aid in maintaining the vicious cycle between activated microglia and damaged neurons (Thundyil and Lim 2015).

The fact that neuronal death can trigger neuroinflammation and that neuroinflammation can, in turn, cause neuronal degeneration, is known as a vicious circle, which is involved in the pathogeny of neurodegenerative diseases (Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Barbeito et al., 2010; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2015).

Microglial cells are involved in the clearance of amyloid plaques (Querfurth and LaFerla, 2010), but can also be responsible for amyloid plaque formation (Streit and Sparks, 1997). As aging microglia seem to lose their ability to phagocytose (Floden and Combs, 2011), impaired clearance, as well as active deposition, can both contribute to amyloid plaque accumulation. 

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?

Quantitative evaluation of these KERs, when KEup and KEdown are measured in the same experiment in a dose and time dependent manner following exposure to DomA or GLF is not available.