The brain contains four large, fluid-filled chambers called ventricles that circulate cerebrospinal fluid (CSF) throughout the brain. This fluid acts like a protective cushion while delivering nutrients to and removing waste from the brain. The brain tissue that borders the ventricles is often one of the first areas to show increased signs of inflammation in AD. Additionally, toxic and neuroinflammatory proteins show up in the CSF at the earliest stages of the disease.
The cells that line the ventricles appear to play a role in these inflammatory responses. Choroid plexus epithelial cells—which produce CSF—help recruit immune cells from the periphery into the brain when inflammation is triggered. The mechanisms by which cells associated with the ventricles regulate neuroinflammation and neurodegeneration remain understudied. Ependymal cells (EPCs), which sit half in the CSF and half in the brain tissue, are responsible for moving CSF through the ventricles. However, their function later in life in brain health and disease is not clearly understood. There is evidence connecting EPC-mediated inflammation to multiple sclerosis, but its role in AD is currently understudied.
Prior to this current project, Dr. Schafer studied the role of complement proteins in microglial-mediated neuroinflammation. As part of that work, her team wanted to determine the source of key complement proteins. Unexpectedly, they found that EPCs produced large amounts of C3, a complement protein whose activity is pivotal for the induction of traditional complement signaling cascades, which boost immune responses to pathogens. In aggressive amyloid pathology models and with age, EPCs increased their production of C3, suggesting that they may play a role in AD. Following her original study, she discovered that microglia adjacent to EPCs adopt a pro-inflammatory state, even before amyloid plaques accumulate, indicating that inflammation is not driven solely by amyloid.
Here, Dr. Schafer and her team hypothesize that EPCs are critical cellular conduits that initiate and propagate neuroinflammatory signals in the brain during Alzheimer’s. Their goal is to identify novel inflammatory signals from the EPCs and ventricular walls that can serve as potential biomarkers or therapeutic targets. Dr. Schafer proposes two primary aims in pursuit of this goal. In the first aim, her team will confirm her preliminary findings that EPCs upregulate C3 and that neighboring microglia adopt pro-inflammatory states in two mouse models of amyloid pathology, as well as in a model of tau pathology. Then, her lab intends to knock out C3 in EPCs and determine if that is sufficient to alter the progression of pathology in the various mouse models. The project’s second aim will establish and confirm the human relevance of Dr. Schafer’s findings in EPCs. Her team will use human brain ventricular wall tissue to determine gene expression patterns in EPCs and confirm their relevance to AD. In addition, Dr. Schafer will be collaborating with CureAlz-funded investigators, Drs. Maria Lehtinen and Liisa Myllykangas. Their collaboration will incorporate proteomics to assess protein changes in the same patient samples. For genes identified as significantly altered in EPCs, a library will be developed for future validation in both mouse and human tissues.
This project examines the role of a vital yet understudied cell type in AD-related neuroinflammation. It also offers the long-term potential to yield novel biomarkers and therapeutic targets for the treatment of the disease.
