Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease

• Type of Material: Article
• Authors: Stacey J. Sukoff Rizzo, University of Pittsburgh; Gregg Homanics, University of Pittsburgh; David J. Schaeffer, University of Pittsburgh; Lauren Schaeffer, University of Pittsburgh; Jung Eun Park, University of Pittsburgh; Julia Oluoch, University of Pittsburgh; Tingting Zhang, University of Pittsburgh; Annat Haber, The Jackson Laboratory; Nicholas Seyfried, Emory University; Benedict Paten, University of California Santa Cruz; Anna Greenwood, Sage Bionetworks; Takeshi Murai, University of Pittsburgh; Sang Ho Choi, University of Pittsburgh; Hasi Huhe, University of Pittsburgh; Julia Kofler, University of Pittsburgh; Peter L. Strick, University of Pittsburgh; Gregory W. Carter, The Jackson Laboratory; Afonso C. Silva, University of Pittsburgh
• Language: English
• Date: 2023-07-01
• Publisher: Wiley Periodicals LLC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/trc2.12417
• Title of Journal or Parent Work: Alzheimer's and Dementia: Translational Research and Clinical Interventions
• Volume: 9
• Issue: 3
• Start Page: e12417
• End Page: e12417
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health, National Institute on Aging U19AG074866 and UPMC‐ITTC IPA 2019 NO.16.
• Keywords: genetic engineering; marmoset; biomarkers; animal models; multi‐omics; PSEN1; Alzheimer's disease; iPSC; cognition
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Introduction: Our limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non-human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD. Methods: A new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO-AD). This consortium will study gene-edited marmoset models carrying genetic risk for AD and wild-type genetically diverse aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD. Results: The consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community. Discussion: By establishing marmoset models of AD, we will be able to investigate primate-specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.