A microphysiological model of the brain-lymphatic system in Alzheimer's disease

Summary The nervous system interacts with the immune system in ways that have been identified to contribute to a number of diseases, including Alzheimer’s disease, infection, brain cancer, and multiple sclerosis. The field of neuroimmunology is a quickly growing research area that involves complex models and manipulations, most often using in vivo models in mice. These models, though useful, lack human components, and have the added difficulties of complex manipulations, difficulty in modulating individual organs without affecting others, and difficulty in the acquisition of dynamic data. In contast, organ-on-chip systems offer benefits in these areas as well as flexibility of cellular components and experimental conditions, but have rarely been applied to neuroimmunology beyond models of the blood-brain barrier. Here we propose to develop a microphysiological system that recapitulates the brain-meninges-lymph node axis in both healthy conditions and in a model Alzheimer’s disease. To do so, we will integrate three tissue engineered models recently established in our laboratory – of the human brain, lymph node, and meninges – into a user-friendly microfluidic device for media recirculation, and validate the function of each compartment separately and together. We will deliberately retain modularity of the system, so that we can examine the interactions of these components while easily manipulating single organ compartments with fluid flow, drugs, mutations, or disease states. We will characterize the response of each component to fluid flow, enable T cell circulation between organs, and test the response to inflammation of each component separately and together. Next, we will convert the baseline model into an Alzheimer’s specific model by incorporating a suite of tissue engineered models of Alzheimer’s brain, derived from neural stem cells from individual Alzheimer’s patients. After confirming lymphatic drainage of amyloid similar to what has been shown in vivo, we will quantify the impact of the Alzheimer’s brain on the inflammatory state of the meninges and draining lymph node compartments, and determine the physical and chemical requirements for biomimetic T cell migration into and within the brain. If successful, we will have both a baseline “normal” system linked through multiple compartments and created from all-human components, poised as a foundation for future use across neuroimmunological research, and a model of interactions between the brain, meninges, and cervical lymph nodes in Alzheimer’s Disease. Ultimately, we envision using these systems for mechanistic tests of disease onset and progression, as well as to test variations in drug responses between individuals of varied ancestry, sex, and age, by sourcing cells from patients representative of different cohorts.