Establishing the marmoset as a non-human primate model of Alzheimer's disease

Abstract

BACKGROUND: There has been a growing interest in the utility of the common marmoset (Callithrix jacchus) as a model system for Alzheimer's disease (AD). As a translational model for AD, marmosets retain anatomical and functional organization of the primate brain that better aligns with humans to enable improved studies of higher order cognitive processes, are maintained as outbred populations which better aligns with the genetic heterogeneity of human patients, and spontaneously present with Aβ deposits and hyperphosphorylated tau aggregates in brain with aging. Recently, viable genetically engineered marmoset lines have been reported including generation of PSEN1Δ9 founder marmosets (Sato et al bioRxiv 2020). Here we report the successful generation of two founder lines of marmosets carrying C410Y and A426P knock-in (KI) point mutations in PSEN1. METHOD: To generate the C410Y or A426P mutations, the CRISPR/Cas9 system was used. Briefly, for the conversion of Cys 410 to Tyr, a G to A substitution of nucleotide 1502 of marmoset PSEN1 cDNA was required; while for conversion of Ala 426 to Pro, a G to C substitution of nucleotide 1549 was required. A comprehensive phenotypic characterization is being conducted from birth including the assessment of developmental milestones, and followed by a longitudinal battery of neuroimaging (PET/MR), fluid biomarkers, and behavioral and cognitive assessments through adolescence and aging. RESULTS: To date we have successfully generated n=3 PSEN1 C410Y (n=2 male, n=1 female), and n=3 PSEN1 A426P (n=2 females, n=1 male) marmosets. Evaluation of plasma Aβ levels before 1 year of age revealed increases in plasma Aβ42 as well as a related increase in plasma Aβ42:40 ratio, relative to age- and sex-matched non-carrier, wild-type (WT) controls. This was similarly observed from fibroblasts derived from skin biopsies from these same individuals. CONCLUSION: The combined efforts and success with generating genetically engineered marmoset models of AD by our group and others, along with comprehensive longitudinal phenotyping in line with clinical AD staging, will be invaluable resources to the research community to study primate specific processes at the molecular and cellular level and ultimately enable improved translational studies for the treatment of AD.