Project Summary The goal of this proposal, at the end of the Phase II effort, is to have a service available to academia and industry to screen drugs for Alzheimer’s to predict patient outcomes and determine how potential therapeutics are delivered to the CNS. There are currently few companies able to offer multi-organ evaluation with a recirculating medium utilizing functional readouts, and none that address aged conditions. Oral delivery is often the preferred route of delivery for drugs and a test platform that emulates both oral and intravenous delivery will be important to pharmaceutical customers. We seek to leverage Dr. Morgan’s research on Alzheimer’s and aging from the Byrd Alzheimer’s Institute and combine it with Drs. Shuler and Hickman’s research on human- on-a-chip systems to better understand the disease and its mechanism of action and to test efficacy and toxic side effects of treatments. We will collaborate with Dr. Schmidt from the Center for Pharmacometrics & Systems Pharmacology at University of Florida for translation of our results for systems pharmacology for AD target discovery in collaboration with our pharma partners. Development of a low cost, easy to use system to assay drugs for efficacy, toxicity and transport for AD would facilitate widespread usage and maximize the benefit to the AD drug development community as well as eventually for patient specific treatments. By eventually comparing acute to chronic effects, the model will enable prediction of clinical trial success using pharmacodynamic (PD) models to inform clinical disease trials from preclinical studies. We have previously constructed platforms demonstrating the integration of multiple organ mimics for acute responses and will build upon that technology. Phase I of this proposal will establish the basic system of GI tract, BBB and CNS neurons in the same recirculating system as well as develop models of Aβ and tau toxicity with the hypothesis that LTP changes and deficits can predict drug efficacy in an AD phenotype. Phase II will expand on these results to include comparisons to normal phenotypes, Alzheimer's neurons from cadavers and for iPSC derived AD neurons in We will add a liver module to the system for drug metabolite generation and test current therapeutics or proposed therapeutics with our partners for both efficacy and delivery efficiency using the multi-organ system. This platform system would use LTP as the functional readout in addition to cell morphology, viability with the ability to track various biomarkers in the system. Our team contains all of the skill sets to achieve the goals on the grant.