GE Homanics¹, SJ Sukoff Rizzo², AC Silva², PL Strick², GW Carter³, JE Park²

Mutations in the presenilin 1 (PSEN1) gene are the most common cause of familial, early-onset Alzheimer's disease (AD), yet rodent models fail to fully recapitulate human AD pathology because they do not naturally develop amyloid plaques or tau aggregates. The common marmoset (Callithrix jacchus) offers a compelling alternative. It is a small non-human primate whose brain closely resembles the human brain, and it develops spontaneous age-related amyloid and tau pathology. We used CRISPR/Cas9 gene editing to independently introduce two PSEN1 point mutations (C410Y and A426P) — the same single-nucleotide changes found in human patients — into marmoset embryos. Several genetically engineered founders were produced; however, most died prematurely. One C410Y founder survived to adulthood and sired germline offspring. Phenotypic outcomes observed in these animals will be the subject of companion talks. In addition, experiments are underway to develop marmoset models of sporadic, late-onset AD. These nonhuman primate models are unprecedented for studying the earliest molecular events that initiate AD, evaluating preventive interventions, and bridging the rodent-to-human translational gap.

Departments of ¹Anesthesiology and ²Neurobiology, University of Pittsburgh, Pittsburgh PA, 15261. ³The Jackson Laboratory, Bar Harbor, ME 04609.

Funding Support: NIA U19 AG074866 and UPMC-ITTC grant IPA 2019 No. 16.