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P4–427: Evaluation of pro–inflammatory factors IL–1 and IL–6 as biomarkers in Alzheimer's disease using an intranasal cytokine model
Author(s) -
Mitrasinovic Olivera M.,
Hanson Leah R.,
Frey William H.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2169
Subject(s) - autocrine signalling , proinflammatory cytokine , paracrine signalling , neuroinflammation , nasal administration , microglia , cytokine , signal transduction , western blot , inflammation , blood–brain barrier , microbiology and biotechnology , medicine , immunology , neuroscience , biology , cancer research , central nervous system , receptor , biochemistry , gene
In Alzheimer’s disease numerous pro-inflammatory factors are overproduced. Immuno-activation of microglial cells, brain macrophages, especially in areas most proximal to amyloid plaque deposits results in amplification of the inflammatory response via autocrine and paracrine mechanisms of regulation and cell signaling network among glia, neurons and astrocytes. Surface binding of A fibrills or soluble oligomers triggers release pro-inflammatory factors that quantitatively correspond to measurements of mRNA gene expression level and ELISA tests of the released proteins, suggesting that proteins in the extracellular circulation may reflect intracellular neurodegenerative conditions. Objective: To develop an intranasal delivery model of pro-inflammatory cytokines IL-1 and IL-6 in normal mice to induce “isolated” proinflammatory conditions and explore usefulness of these factors as predictors of neuronal dysfunction while validating laboratory outcomes with computational predictions based on system biology calculations. Methods & Results: The experimental model is based on intranasal delivery of therapeutic peptides and proteins that has been demonstrated in animals and humans to bypass the blood-brain barrier and target brain. Intranasal delivery utilizes the olfactory and trigeminal neural pathways to extracellularly deliver peptides to the brain. Intranasal delivery can be used to increase pro-inflammatory factors IL-1 and IL-6 in the brains of normal mice in order to determine effects on neuronal survival or apoptosis. We can analyze rapid signaling induction of “small” molecules, such as tyrosine kinases and determine the rate of phosphorylation as a mean to assess activity. Western blot analysis of whole brain extract can be used to monitor protein expression changes. A computational system biology model generated on GEPASI 3.30 simulation established link between reactive oxygen species (ROS) and JNK activation and that ROS induce cross-talk in MAPK integrated JNK/NF B signaling. Conclusions: Usefulness of intranasal delivery is assessed as an approach to study biochemical pathways following neurodegeneration and in determining neuronal effectiveness of pro-inflammatory factors released by microglia. Induction of these factors may signal an early event in neurodegeneration, making studies of their suitability as biomarkers feasible. A computational approach can be used to validate laboratory findings. Identification of the signaling components may open possibilities for novel targeted therapeutic interventions.