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

National Institute On Aging

Investigators

Abstract

Toward our aim of developing a neuronal model to quantify and induce cellular senescence, we have explored senescence induction with two types of stimuli ad different doses: doxorubicin treatment and SLO treatment. We assessed senescence signatures using multiple methods: transcriptomic, proteomics, activity assays, and immunofluorescence. We show that neurons display unique signatures associated with stress and senescence, and identify conserved markers across induction methods. Next, with signatures in hand, we will probe the extent to which ADRD lines from iNDI express senescence signatures at baseline to identify ADRD variants with a propensity for senescence. Thus far we have shown that one mutation, GRN1, enhances senescence signatures in neurons exposed to senescence-inducing stimuli. These results suggest that one mechanism by which common ADRD-related mutations lead to disease may be by sensitizing neurons to cellular senescence. In ongoing work, we will also probe existing proteomic and transcriptomic datasets from human ADRD populations to determine whether increases in senescence signatures are associated with disease. In the future, we will systematically test the propensity of other ADRD risk variant-engineered cells to become senescent based on these signatures. The proposed work would systematically screen for the extent to which mild stress (doxorubicin treatment) induces senescence in genetic variants associated with ADRD, and help determine which genes are mechanistically linked to cellular senescence as a potential driver of aging. Toward the AIM of identifying secretomes associated with ADRD variants, we have received conditioned medium from iPSC-derived astrocytes derived from iNDI lines. We are developing a protocol to comprehensively proteomic profile the secretomes.