Overview
CSF bathes the entire central nervous system, providing a rich menu of active factors for brain cells and promptly removing their wastes. Most of CSF is produced by the choroid plexus, a secretory epithelial tissue that also forms the blood-CSF barrier to selectively gate the entry of not only blood-borne molecules, but also peripheral immune cells, into the brain. We use longitudinal in vivo imaging approach combined with neuroimmunology and multi-omics tools in rodent models and human tissues to answer the pressing questions: how do brain aging and Alzheimer’s disease drive choroid plexus dysfunction? How does choroid plexus dysfunction harms brain microenvironment and accelerate neurodegeneration? Can we reverse or supplement for the deficits by taking advantage of the choroid plexus and its exceptional ability to secrete factors? Together, we aim to discover mechanisms to fine-tune brain microenvironment and inspire new therapies.
1. Epithelial-immune synergy in blood-CSF barrier health
The choroid plexus (ChP) makes up the main part of the blood-CSF barrier through its epithelial tight junctions. Resident macrophages and other immune cells at the ChP closely interact with epithelial cells to modulate barrier integrity, especially during brain inflammation. Here, we investigate the mechanistic underpinnings of ChP barrier maintenance and disruption by resident and infiltrated immune cells in aging and Alzheimer’s disease. We employ longitudinal in vivo two-photon imaging of the ChP and brain ventricular space to monitor cellular behaviors in real time, and combine with multi-omic and neuroimmunology tools to discover the molecular mechanisms that guide the behaviors.
Sneak a peek at the ChP in action
We use in vivo longitudinal two-photon imaging to watch cells at the ChP go through their everyday life and identify abnormal behaviors. We seek to connect behaviors to molecular changes and understand their functional impacts.
2. The causes and consequences of a fibrotic ChP
Aged choroid plexus (ChP) is fibrotic. This is as much as we know. How it happens, and more importantly, how it changes ChP function and brain function, remains a complete mystery. We can guess that the accumulation of fibrotic tissues will cut off the communication between blood supply and epithelial cells, and thereby significantly change the ChP secretion. To test these hypotheses, however, we need new tools to model ChP fibrosis in a controllable manner in vivo. This project aims to create new mouse models that recapitulate ChP fibrosis through genetic manipulation and interrogate how ChP fibrosis impacts the brain.
How to create ChP fibrosis in vivo?
There is no directly available mouse models that create ChP fibrosis, unless the mice are aged to over 24 months! Our goal is to create a model combining genetic and AAV approaches.
3. ChP-brain crosstalk through the brain’s fluids
The choroid plexus (ChP) is a highly secretory epithelium that produces the majority of CSF, including both the bulk volume and the numerous active factors within. CSF bathes the entire central nervous system, modulating the microenvironment for all brain cells. We aim to develop new tools to investigate two ways the ChP communicates with the brain: (1) how ChP secreted factors exert their effects on brain cells through CSF, especially those that are highly or almost exclusively expressed by the ChP and are implicated in aging and Alzheimer’s disease, such as APOE, TTR, and klotho. Conversely, we are also interested in how signals of brain origin influence ChP barrier functions and subsequently talk to the periphery. (2) as a main gateway for periphery immune cells to enter the brain, what roles does the ChP play in coordinating immune cell movements and communication between the body and the brain?
How to follow cells and molecules after they leave the ChP?
We aim to develop new in vivo tools to track the whereabouts of molecules and cells that are produced or transported by the ChP into CSF, the brain parenchyma, and its interstitial fluid.
