Engineering a Vascularized Brain-Chip for Probing and Evaluating Mechanisms of Alzheimer’s Disease

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An estimated 1 in 10 Americans age 65 and older are currently living with Alzheimer’s Disease (AD), yet there is still no pharmacologic treatment available that can slow or stop the neuronal damage in AD. A number of drugs targeting AD that showed promising results in mice have failed to prevent cognitive decline in clinical trials. We still do not understand the molecular mechanisms underlying AD and current in vitro systems fail to recapitulate the complexity of the disease. An in vitro human brain model that recapitulates AD pathology could enable the elucidation of mechanisms of AD and provide a tool for drug testing and discovery for improved clinical outcomes. Recently, collaborator Li-Huei Tsai developed a model of the brain with all seven relevant neural cell types (miBrain). Engineering a brain-mimetic hydrogel scaffold and introducing flow into the system are desired to enhance the physiological relevance and cell phenotypes. A novel brain-mimetic hydrogel scaffold will be engineered, which, unlike current alternatives, will not contain deleterious extracellular matrix (ECM) components like fibrinogen and will have tunable degradation kinetics and less batch-to-batch variability. iPSC technology will be used to create models that each contain cells from a single individual and that will be created for individuals from diverse genetic backgrounds. Combining iPSC technology and a brain-mimetic scaffold in a perfusable platform, will result in a system that could enable the study of AD mechanisms and evaluation of therapeutic treatments. This model will be deployed to interrogate the pathway involving APOE4-promoted pathogenesis, the strongest genetic risk factor for late-onset AD, assessing the impact of APOE variant and key molecular regulators on AD pathological signatures. The model will be further harnessed to assess the effect of ECM components on AD pathogenesis and profile changes in ECM, as AD is associated with changes in AD but heretofore there has not been an in vitro model to probe the effects or causes of these changes. This work will result in the development of a novel perfusable miBrain model that can be harnessed to study and test therapeutics for AD, dissecting underlying molecular pathways and assessing disease pathogenesis and neuronal activity. The combined hydrogel scaffold, chip platform, and iPSC technology provide a powerful approach to mimicking the brain that can be rapidly deployed to probe a broad variety of questions related to neurovascular mechanisms, neural cell type interactions, and neurological diseases. For training, this project enables the synthesis of fields, combined in ways that lead to gaining new expertise in each area while developing a novel research niche with many potential future directions. The project will be executed in a world-renown training environment and with a comprehensive training plan that includes helpful techniques, courses, conferences, seminars, journal clubs, and lab and individual meetings. This is all designed to launch an academic scientist career of developing technologies that enable probing neurobiological mechanisms, therapeutic discovery, and improved disease treatments and of training future scientists.