MPS Models Development and Validation Core

ABSTRACT MPS MODELS DEVELOPMENT AND VALIDATION CORE With the advancement of robust differentiation protocols and the generation of large cohorts of iPSC lines, the field now stands ready to utilize iPSC technology for the purpose of disentangling person-specific or subtype- specific processes driving risk and resilience for Alzheimer’s disease. To this end, we have recently generated a cohort of iPSC lines from over 100 individuals of diverse ancestry from the ROS and MAP cohorts of aging. These cohorts are deeply phenotyped with acquisition of longitudinal cognitive data, quantitative neuropathological measurements, and multi-omics data acquired from brain tissue and plasma. The goal of the MPS Models Development and Validation Core is to develop robust and reproducible human cellular experimental systems for testing therapeutic strategies across diverse genetic backgrounds. Three experimental systems that be utilized are 1) a reductionist 2D co-culture system of neurons, astrocytes, and microglia; 2) a Brain-Chip system that incorporates neurons, astrocytes, microglia, pericytes, and endothelial cells that form a layered blood-brain-barrier (BBB) on a two-chambered microfluidic device; and 3) a 3D engineered organoid system, the multi-cellular integrated Brain (MiBrain), which incorporates up to seven different cell types. We employ these three systems which each have unique advantages and disadvantages with the understanding that different therapeutic strategies may require different experimental setups in order to accurately and reliably relay target engagement, efficacy, and safety. The activities of this core fall under four specific aims. First, this core will generate key foundational data for each experimental system using both multi-omic, unbiased approaches and directed biomarker measurements to define the molecular signatures of brain cells across diverse genetic backgrounds. These measurements will be coupled to functional measurements of biological domain disruption. In aims 2-4, we will develop preclinical efficacy assays for testing of interventions for AD that target three different processes: 1) Ab levels, 2) synaptic vulnerability, and 3) microglial dysfunction. We will define the molecular signatures of human brain cells in response to six interventions that span these three biological domains. Data generated under this core’s activities will be analyzed within the Biostatics and Computational Biology Core, where it will be integrated with omics and biomarker data from human natural aging studies as well as biomarker data from individuals receiving some of the same interventions. Protocols for the cellular models and top performing assays established here will be shared with and scaled within the Preclinical Efficacy and Safety Core, to allow for the testing of interventions across >100 genetic backgrounds using biomarker readouts of responsiveness established under the MPS Core’s activities. The Administrative and Data Management Core will provide oversight and guidance on this core’s activities, and will establish efficient pipelines for distribution of data, protocols and cell models.