PROJECT SUMMARY The goals of the Program Project are to understand the causes and consequences of cellular senescence as a driver of age-related neurodegeneration, determine new targets and mechanisms by which senescent cells drive disease, and identify new targets for interventions that alter disease onset and/or progression. The Alzheimer’s disease and related dementias (ADRD) induced pluripotent stem cell (iPSC)/organoid core, led by Drs. Ellerby and Tracy, will provide expertise in generating iPSC-derived neurons, astrocytes, microglia, co-cultures and brain organoids to understand cellular senescence as a driver of age-related neurodegeneration. It will provide a suite of iPSC cellular models to all three projects and validate all the derived cell types, co-cultures and brain organoids. The Core will provide essential infrastructure, training and support for all scientists participating in the PPG. In addition, it will provide everything needed to culture, conduct electrophysiological recordings, and image cells. The Core directors have experience in all of these cell manipulations and will approve all Alzheimer’s-related disease (ARD) and control iPSC models for the facility, including live and frozen cell cultures from commercial and academic sources, to ensure reproducibility, authentication, testing for mycoplasma, and other cell line maintenance and validation tasks. These Core directors will approve all Alzheimer’s disease related and control iPSC models for the facility, including live and frozen cell cultures from commercial and academic sources, to ensure reproducibility, authentication, testing for mycoplasma, and other cell line maintenance and validation tasks. The Core will train students and postdoctoral fellows and oversee any research involving iPSCs that require ESCRO approvals, ethics training and MTAs. To accomplish these goals, five specific aims of the ‘ADRD iPSC/Organoid Core’ are described. These goals are organized around the cell type or technology that is needed to address the research questions described in the three projects in an efficient and optimized approach. The Specific Aims of this Core are: Specific Aim 1 – Generate a bank of iPSCs derived from the indicated models; Specific Aim 2 – Microglia. Generate microglia from iPSCs derived from the models (Projects 1, 2 and 3); Specific Aim 3 – Astrocytes. Generate astrocytes from iPSCs derived from the models (Projects 1 and 3); Specific Aim 4 – Cortical Neurons. Generate cortical neurons (excitatory and inhibitory) from iPSCs derived from the models (Projects 1, 2 and 3); Specific Aim 5 – Cerebral Organoids and Co-cultures. Provide cerebral organoids (Projects 1 and 3); Specific Aim 6 – Electrophysiology and Imaging. We will perform electrophysiological recordings for Projects 1, 2 and 3 in both human cellular models and mouse models. These aims will provide models and technology that will enhance our knowledge of cell type specificity and interactions in AD cel...