The Effect of Novel Anti-Inflammatory Drugs on Alzheimer's Disease

Abstract

Alzheimer's Disease is a neurodegenerative disease characterized by cognitive, functional, and neuronal loss. Its core pathology includes beta-amyloid protein plaque formation, neurofibrillary tangles of tau protein, and loss of microglial cell function, all of which may be facilitated or exacerbated by a prolonged neuroinflammatory response. The inflammatory signaling pathway culminates in the activation of transcription factor NF-B, which then goes on to activate the expression of cytokines and other signaling molecules such as TNF. One of the points of regulation for this pathway is the binding of the IB protein to NF-B that prevents NF-B from entering the nucleus. However, when the appropriate stimulus triggers the pathway, a downstream effect is the phosphorylation of IB by the IB kinase, and its subsequent degradation which then releases NF-B for translocation into the nucleus. This project aims to elucidate the mechanism of action of novel anti-inflammatory drugs (provided by P2D Biosciences company). Previous in vivo studies with the compound have shown a reduction in inflammation and improved cognition, but the drug's exact point of interference in the pathway remains unclear. We hypothesize that the drugs reduce inflammation by reducing IB degradation, thus preventing NF-B from being able to turn on cytokine expression. BV-2 mouse microglial cells were exposed to the drugs, followed by exposure to LPS for various time intervals, then harvested and lysed. A Western blot procedure was performed on the lysates to visualize the amount of IB present, then those bands were quantified to compare against control cells that were not incubated with the drug. It follows then, that if the drugs' mechanism of action is inhibition of NF-B release into the nucleus, then there will be increased amounts of IB in the treatment cells compared to the control cells as IB degradation is prevented.