A non-human primate model of familial Alzheimer’s disease for translational medicine

Abstract Aging is a primary risk factor of Alzheimer’s disease (AD), with the world-wide number of patients anticipated shortly to exceed 50 million. Despite extensive research efforts, no effective measures are available for its prevention or treatment due in part to a lack of human-like animal models. Here, we describe the generation of three mutant marmoset individuals in which exon 9 of the PSEN1 gene product is deleted (PSEN1-ΔE9); the ΔE9 mutations have been reported to cause early onset familial AD1-5. We used Transcription Activator-Like Effector Nuclease (TALEN) to delete the 3’ splice site of exon 9 in the marmoset PSEN1 gene; to this end, TALEN exhibits high genome-editing efficacy, generates few off-target effects, and produces minimal mosaicism. Indeed, whole genome sequencing and other analyses illustrated an inclusive absence of off-target effects and apparent absence of mosaicism. Fibroblasts obtained from newborns indicated occurrence of full-length presenilin 1 protein (PS1) caused by perturbation of PS1 endoproteolysis as well as an increased ratio of Aβ42/Aβ40 production, a signature of familial AD pathogenesis. To our knowledge, this is the first non-human primate model of familial AD. The model lines will be made available to the research community to facilitate the global fight against AD.