CARD - Senescent Phenotypes of Isogenic iPSC-Derived Alzheimer's Disease and Related Dementia Models at Cellular Resolution

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Toward our aim of determining which genetic risk variants of ADRD sensitive cells to senescence, we have created a pilot experimental plan for the establishment and optimization of iPSC-derived neuronal senescence in the KOLF2.1j parental line. Using genotoxic stress induced by doxorubicin treatment, we found the optimal dose of senescence to induce a stable senescent phenotype in culture is between 25nm to 50nm. We have prepared proteomic and transcriptomic samples accross the entire dose response, as well as imaging data to confirm the presence of senescence signatures. From the resulting data, we will develop multi-omic (proteomic and transcriptomic) signatures of senescence in neurons, and then systematically test the propensity of other ADRD risk variant-engineered cells to become senescent based on these signatures. The proposed work would systematically test whether genetic variants associated with ADRD are mechanistically linked to cellular senescence as a potential driver of aging.