Dr. Lehtinen’s project spotlights the choroid plexus barrier in the brain. The choroid plexus resides in each brain ventricle and is responsible for producing cerebrospinal fluid (CSF). It is comprised of epithelial cells, immune cells, and blood vessels and, therefore, also provides a barrier between the blood, CSF, and brain. Some research suggests that inflammation of the choroid plexus impairs its barrier function, allowing peripheral immune cells to enter the brain and that these events are involved in neurodegenerative diseases. However, despite many hints of a role for the choroid plexus in mediating inflammatory effects on the brain, it has not been widely studied in the context of Alzheimer’s disease (AD), likely due to the limited availability of human choroid plexus samples and the technical hurdles of studying the choroid plexus in mice. With CureAlz funding, Drs. Lehtinen and Myllykangas teamed up to tackle these two issues. The Myllykangas lab has a unique tissue repository with choroid plexus samples from over 300 human subjects (from Finland), and the Lehtinen lab has deep expertise in mouse models and the advanced imaging methods needed to observe the choroid plexus.
They proposed three aims to explore the role of the choroid plexus in AD. In the first aim, they are assessing the integrity of the choroid plexus and identifying the types of immune cells present in Alzheimer’s human samples and amyloid mouse models. In the second aim, they are tracking the numbers and location of immune cells in and around the choroid plexus in living mice and determining how their movements and functions change in the presence of amyloid. In the third aim, they are identifying which proteins in human choroid plexus cells change in abundance with the progression of AD.
Over the first year, the team used in vivo two-photon imaging to track resident macrophages in the choroid plexus of 5xFAD mice, revealing signs of barrier dysfunction and immune cell clustering as amyloid pathology increased. This work lays the technological foundation for studying immune cell behavior in AD and other neuroinflammatory conditions. Moving forward, they will quantify and characterize additional immune cell populations in the choroid plexus and analyze human patient data to identify key molecular pathways for future study.
