RON’S INVOLVEMENT IN THE INFLAMMASOME PATHWAY ATTENUATES ALZHEIMER’S-ASSOCIATED NEUROINFLAMMATION
Open Access
- Author:
- Hare, Amelia June
- Area of Honors:
- Immunology and Infectious Disease
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Dr. Pamela A. Hankey-Giblin, Thesis Supervisor
Dr. Pamela A. Hankey-Giblin, Thesis Honors Advisor
Dr. Robert F. Paulson, Faculty Reader - Keywords:
- Macrophages
Neuroinflammation
Inflammasome
RON
Alzheimer's Disease
microglia - Abstract:
- Out of the top 10 causes of death in the United States, Alzheimer’s Disease (AD) is the only one that currently cannot be prevented, slowed, or cured. Ongoing research to unravel this complex and devastating illness has shown that a chronic state of inflammation contributes to worsening pathological conditions of AD and may even provoke an earlier onset of the disease. Therefore, understanding the cellular signaling pathways involved in mitigating inflammation in the brain could elucidate new potentials for preventative therapies or novel drug targets in AD. One pathway of interest involves the RON receptor tyrosine kinase (RON) expressed on macrophages. Previous studies have demonstrated that RON knockout mice exhibit more inflammation than their wild type counterparts, suggesting that RON plays a protective role in attenuating the inflammatory state. Although we know that RON is at the beginning of a pathway that quells inflammation, the downstream events of this pathway are largely unknown. Therefore, this study aimed to elucidate the downstream regulatory effects of RON by establishing a connection between RON and another hallmark inflammatory pathway known to occur in macrophages. We hypothesized that RON was involved in suppressing signal 2 of the inflammasome pathway, thus limiting inflammasome activation. Using an atherosclerosis model to simulate a chronic inflammatory state, whole brains and brain regions were harvested from control and RON-KO mice and analyzed for expression levels of key inflammasome-pathway proteins (including NLRP3, IL-1β, and caspase 1) using western blot analysis. The results show that, in the whole brain, hippocampus, and hypothalamus, RON-KO mice express higher levels of NLRP3, cleaved caspase 1 and cleaved IL-1β, indicating that RON plays a role in suppressing not only the expression of these inflammasome proteins, but also their activation. These novel results are the first to demonstrate RON’s involvement in signal ii 2 of the inflammasome pathway in the brain, and shed new light on the function of the RON receptor and its potential to alleviate the inflammatory state implicated in the early stages of AD.