PROJECT SUMMARY ASSAY CORE The Emory-Sage-SGC-Jax TREAT-AD Assay Development and Screen Core (Assay Core) serves as a technology platform to provide innovative and informative assays for target assessment, for high throughput screening of challenging targets and evaluation of biological perturbagens, and for functional characterization of biological and chemical probes in in vitro and in vivo models. The Assay Core has established an innovative operational structure that harnesses a wide range of expertise and capabilities for AD target evaluation and chemical and biological probe discovery from both public and private sectors. The Core will be organized with an operational hub at Emory University and spokes of expanded capabilities with world-leading Associated Partners, who will contribute specialized assays, screens, and biological expertise. Associated Partners include the University of Pittsburgh with AD animal models for in vivo target engagement and efficacy studies, the University of California San Francisco for expertise in CRISPR-based functional genomics in human iPSC- derived neural cells, the Jackson Laboratory for bioinformatics and data analysis, the University of Washington for in-depth target biology, and the Structural Genomics Consortium (SGC) for rich experience in diverse assays and screens. With our demonstrated capabilities and combined complementary expertise and integrated operation with Bioinformatics, Structural Biology, Med Chem, and Admin and Data Cores, we will support the overarching goal of TREAT-AD by developing hypothesis-driven and informative assays, creating experimental reagents, and validating probes to populate Target Enabling Packages (TEPs) for each prioritized target to catalyze robust evaluation of a diverse set of therapeutic hypotheses. The Assay Core aims (i) to provide experimental assay evidence in AD-relevant cell systems to advance nominated targets through a tiered pipeline to enable target identification and prioritization, (ii) to evaluate validated tools/probes that enable modulation of targets, (iii) to support studies of the disease-modifying role of identified biological or chemical probes in AD pathogenesis for target prosecution and biological insights. Over the 5-year project, completion of these aims will generate experimental evidence for up to 100 nominated targets (~10-20 per year) for development of assay packages and will test a minimum of 5 target-specific probes per year. For each target, all reagents and tools will be released as TEPs to the scientific community.