Genomic analysis of fibroblasts from marmosets carrying early‐onset Alzheimer’s disease mutations in PSEN1

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia and remains generally untreatable. The slow, age‐related development of AD and inaccessibility of early‐stage brain tissue has limited our understanding of its origins and progression. Large‐scale genetic studies and molecular analysis of postmortem brain samples have nominated dozens of candidate genes and proteins for therapeutic targeting or diagnostic biomarkers, generating a need for in vivo systems to study the underlying biological dysfunction and perform preclinical testing. Here, we report on genetic, genomics, and proteomic analysis of fibroblast lines derived from a colony of marmosets genetically engineered with rare familial variants in the PSEN1 gene.MethodWe performed whole‐genome sequencing on 14 individuals, including six mutant carriers. We validated the presence of the PSEN1 mutations and assessed variation at multiple other Alzheimer’s disease loci. Fibroblast cultures were obtained from 12 animals and assayed using a Nanostring AD gene expression panel and label‐free proteomics. This allowed us to quantify 800 transcripts and 2165 proteins per sample.ResultWe detected differential gene expression for genes enriched in neuron development and amyloid‐beta regulation, providing strong evidence for the functional relevance of the engineered variants. We quantitatively compared changes in marmoset PSEN1 fibroblasts to similar molecular measures in postmortem brain tissue and induced pluripotent stem cells (iPSCs) from human AD studies. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with changes in iPSCs from human AD carriers reprogrammed into neuronal lineages. We also observed both transcriptomic and proteomic changes in marmoset PSEN1 cells that match those in postmortem AD brains.ConclusionThese findings demonstrate that disease‐relevant pathways and processes are altered in fibroblasts from mutant marmosets, provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset‐derived cell models, and outline a strategy to align marmoset models with human disease to facilitate robust translation.