Pro‐inflammatory IL‐1α signaling alters cellular homeostasis of NF‐kB: the AI evaluation study

Abstract

AbstractBackgroundIncreased CSF levels of interleukin‐1α (IL‐1α) in Alzheimer’s Disease (AD) have been attributed to sustained inflammation, hallmark accompanying two main disease pathologies, Αβ and p‐τ, and leading to behavioral disturbances and progressive memory loss. Disease‐repair mechanisms elicited by neurons, astrocytes or microglia have been long‐term interest of pharmaceutical companies, however, NSAIDs anti‐inflammatory therapies showed limited benefit. Aside from inducing pro‐inflammation, extracellularly membrane bound IL‐1α:IL1R activates intracellular anti‐apoptotic neuroprotective transduction pathways, affecting cell growth, differentiation, and clearance of Αβ. Distinguishing beneficial vs. cytotoxic inflammation has importance in the design and improvement of AD medications.MethodBased on our previous findings on [IL‐1α] → [ NF‐kB] interactions, also our laboratory data, and cumulative literature data for IL‐1α, we have applied a computational AI approach to identify downstream components of the pathway affected by inflammatory response and signal transducing interactions. High‐throughput algorithmic calculations (AAIC2020 abstract #39142) were performed in the MATLAB® platform, and output data graphed in Excel as 2D or 3D connectivity diagrams, allowing monitoring kinetics of interactions and cytokine dose‐dependence. Data were validated by comparative traditional laboratory assays.ResultExtracellular‐membrane IL‐1α :IL1R receptor binding, shown in MATLAB (MathWorks) as disappearance of free, and accumulation of complex bound IL‐1α correlates with cytoplasmic transport of NF‐kB to cell nucleus. Pro‐inflammatory inducer LPS, did not produce the same outcome, in agreement with our previous laboratory studies that showed unique pattern of synergistic IL‐1α ←→ M‐CSF growth factor induced pro‐inflammation that activates neurotrophins. Exploration of signaling connectivities showed that IKK, ΙκΒ components in NF‐kB anti‐apoptotic pathway are affected by IL‐1α in [time] and [concentration] dependent manner, demonstrating further ability of algorithm to sequentially map order of interactions. 3D connectivity graphs show NF‐kBn and ΙκB co‐regulated expressions in responds to specific, narrow [IL‐1α] → [IKK] concentration interval, allowed identification of the inflection point among variables that distinguish neuroprotection and cytotoxicity.ConclusionOur optimized MATLAB® methodology appears to be a useful assisted collaborative tool in pre‐clinical evaluations, and screening interacting connections among proteins altered during disease mechanism, and identification of new AD pathogenesis‐linked, enabling higher accuracy and lowering overall laboratory costs in search for disease biomarkers.