Microphysiological systems to Advance Precision medicine for Alzheimer's Disease and Related Dementias (MAP-AD)

ABSTRACT MPS Model Development and Validation (MMDV) Core The Microphysiolgical system (MPS) Model Development and Validation (MMDV) Core of the Indiana University MAP-AD Center aims to establish human induced pluripotent stem cell (iPSC)-based 3D models to more effectively study Alzheimer's disease (AD) and Alzheimer's disease releated dementias (ADRD). The MMDV core will develop and optimize robust and reproducible protocol(s) for the scalable generation of standardized MPS models, including the incorporation of 3D printed vascularized perusable scaffolds with adapted human brain organoid protocols. Generation of isogenic iPSC lines will reflect significant genetic risk loci associated with neuroinflammatory and/or cerebrovascular dysfunction profiles in AD/ADRD implicated by prior studies from MODEL-AD, TREAT-AD, and CLEAR-AD Centers at IUSM. To ensure that MPS models recapitulate key features of human AD/ADRD pathophysiology, we will observe neuroinflammatory and cerebral dysfunction phenotypes in our iPSC-derived MPS organoid and barrier models. Neuroinflammatory conditions are common across neurodegenerative disease states and recently, the contribution of neuroinflammation to AD/ADRD pathology has been implicated. Similarly, cerebral vascular dysfunction has been observed to both precede classic AD pathologies and potentially exacerbate AD phenotypes. Following the identification of AD variants with a combination of neuroinflammatory and/or vascular dysfunction we will combine the MPS organoid models with both microglia and cerebrovascular units. The combined perfusable organoid model will permit further phenotyping of critical cytokines, cellular communication, barrier-organoid interactions, and functional connectivity with “brain-like” function. The advanced MPS models will then be transferred to the Preclinical Efficacy and Safety (PES) Core to assist in therapeutic discoveries bridging the gap between traditional preclinical animal studies and human clinical trials. By leveraging expertise in organoid and blood-brain barrier modeling as well as extensive bioengineering expertise, we will generate and characterize MPS models with various genetic factors for AD/ADRD, including detailed phenotyping, single cell transcriptomics, and most importantly, the ability to provide these models and resources quickly to the research community through the NCRAD biorepository and the AD Knowledge Portal.