Investigating the processes of age-related inflammation in the central nervous system

With age, many of our central nervous system (CNS) functions become disrupted, and the CNS becomes inflamed. It is not very well understood what causes this inflammation, however, the offending neuroinflammatory signals, molecules, or cells, responsible can be characterised as either extrinsic, or intrinsic, to the CNS. We first sought to determine if extrinsic components enter the CNS with aging. The CNS is protected from extrinsic factors by the blood-CNS barriers. Breakdown of these would allow neuroinflammatory molecules and cells to enter. Using a variety of molecular and functional techniques, we found the blood-CNS barriers to be largely intact, suggesting the neuroinflammatory signals are likely intrinsic to the CNS. We then took a discovery-driven approach and used RNA sequencing to investigate potential intrinsic mechanisms. We found the aging CNS was characterised by microglial-associated inflammation, upregulation of antigen presentation genes, disruption in proteostasis, and dysregulation of unannotated regions of the genome that are likely long-non-coding RNAs (lncRNAs). We suggest that an inability of the CNS to degrade aberrant proteins may result in antigenic proteins that cause immune stimulation. We also suggest key components of novel microglial pro-inflammatory pathways may be present in non-annotated transcripts that were differentially expressed with age, as lncRNAs are known to drive pro-inflammatory microglial pathways. Finally, given the universality of aging, we assessed how CNS co-regulatory networks change with age across species, using PANDAR. We found 22 transcription factors are consistently involved in aberrant regulatory interactions, and suggest EGR2, GLIS3, KLF2, and KLF6, are potential therapeutic targets due to their expression in 6 inflammatory cells. Overall, we have demonstrated that CNS inflammatory processes are the result of aberrant mechanisms intrinsic to the CNS and have identified several of these processes, including molecules that may be therapeutic targets.