Tau mislocalization assay to screen AD therapeutics using compartmentalized chips

PROJECT SUMMARY: Neurofibrillary tangles, a hallmark of Alzheimer's disease (AD), are formed following tau dissociation from microtubules and mislocalization to the somatodendritic compartment of affected neurons. Pathological tau is then released from affected neurons and spreads trans-synaptically eventually leading to cell death. Preventing the initial mislocalization of intracellular tau within the somatodendritic compartment presents an early therapeutic target and may lead to strategies that limit the progression of AD. Xona Microfluidic, Inc. (“Xona”) proposes to develop a reliable, reproducible, and scalable screening assay to identify and validate therapeutic targets that prevent early mislocalization of intracellular tau. The goal of this project is to establish the feasibility of providing preclinical screening services using this assay for AD and AD-related diseases. Preliminary data suggests that tau mislocalization can be modeled in Xona's proprietary compartmentalized microfluidic chips by restricting exposure of Aβ-induced neuroinflammatory media to the axonal compartment. The resulting tau mislocalization correlates with an increase in synaptic vesicle release, which is consistent with AD pathophysiology. Xona proposes to develop this screen on the basis of this preliminary data and using human induced pluripotent stem cell differentiated neurons cultured in 3D, which more closely mimic human disease phenotypes than murine models. Aim 1 will determine the extent to which 3D cultures improve synapse maturation over 2D cultures using these neurons within our compartmentalized chips. Aim 2 will develop a tau mislocalization assay using Aβ-induced neuroinflammatory media. Further, we will evaluate the reliability and suitability of this assay for drug screening using an established metric of screening potential. Once feasibility is shown, Xona will focus on forming partnerships with potential customers and scaling up the number of compounds that can be screened.