Kumar, S.; Haber, A.; Spruce, C.; Duong, D.; Seyfried, N.; Bailey, L.; Choi, S.-H.; Hachem, S.; Mou, Y.; Ha, S.-K.; Park, J. E.; Homanics, G. E.; Sukoff Rizzo, S. J.; Silva, A. C.; Carter, G. W.

INTRODUCTION: The slow, age-related development of Alzheimer's disease (AD) and inaccessibility of early-stage brain tissue necessitates model studies to understand its origins and progression. Non-human primate models can provide a platform for linking molecular changes to translatable phenotypes. Here, we assess fibroblast lines derived from marmosets with engineered variants in the PSEN1 gene. METHODS: Fibroblast cultures were obtained from 10 animals and assayed using a NanoString AD gene expression panel and label-free proteomics. We compared mutant expression changes to human AD signatures in human iPSC-derived neurons and postmortem brains to assess disease relevance. RESULTS: Gene products involved in amyloid-beta interaction and regulation were differentially expressed, providing evidence for the functional relevance of the engineered fibroblasts. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with human iPSCs from AD donors reprogrammed into neuronal lineages, as well as postmortem brains derived from case-control cohorts. Altered expression profiles were noted based on marmoset donor sex and mutation status, highlighting underlying sex-specific biology relevant to Alzheimer's disease. DISCUSSION: These findings demonstrate that disease-relevant pathways and processes are altered in fibroblasts from mutant marmosets, emphasize the complementarity of transcriptomic and proteomic profiling in AD, and provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset-derived cell models.