Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY OVERALL Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting 6 million Americans with a fast growth over the next several years. Our limited understanding of the mechanisms that trigger AD contributes to the lack of interventions that prevent, delay, or fully treat this disease. In our original application, we proposed to establish the marmoset as the first primate-specific model to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception, drawing from a large marmoset colony with dedicated veterinary and husbandry teams, state-of-the-art in vivo neuroimaging and molecular assays, and a multidisciplinary team of experts in aging biology, AD genetics and genomics, animal model development and characterization, behavioral and cognitive phenotyping, and genetic engineering. Our proposal’s overarching goals are to develop early-onset (EOAD) and late-onset AD (LOAD) marmoset models to enable the investigation of the underlying cellular and molecular root causes of the pathogenesis and progression of AD and support future translational studies. Our proposal consists of 3 integrated Research Projects aiming to: (1) Investigate early-life molecular determinants of AD disease pathogenesis in marmosets harboring PSEN1 mutations that cause EOAD; (2) Identify and enhance LOAD-related signatures in outbred and genetically engineered marmosets; and (3) Conduct a comparative multimodal phenotypic characterization of marmoset models of AD. Five Research Cores have supported these projects focused on project administration, bioinformatics, genetic engineering, multimodal disease characterization, and veterinary care and colony management. These cores generate novel gene-edited marmoset AD models, develop optimized protocols for studying disease onset and trajectory in line with clinical protocols, and provide specialized animal care and support, allowing complete characterization of the marmoset models. The cores also integrate marmoset and human genomic signatures, providing data dissemination and resources to the greater research community. In the present competing revision, we introduce a new Cellular Modeling Core (CMC) to support the in vitro phenotypic characterization of our marmoset AD models. The CMC will obtain longitudinal fibroblast skin biopsies from living marmosets and post-mortem primary astrocyte and neuronal cultures and use state-of-the-art protocols to optimize cellular reprogramming and differentiation techniques to study cellular mechanisms of AD. The CMC will also establish a pipeline for the comprehensive characterization of amyloid-β generation, pathological tau accumulation, neuroinflammation, and neuronal stress in both primary and differentiated cellular cultures throughout the lifespan of each animal. The CMC aims to maximize the usefulness of marmoset AD models by creating a robust pipeline leveraging the use of cells as surrogates of brain trajectories during the marmoset lifespan and development of AD. Work in the CMC will be invaluable to elucidating cell-specific pathogenic mechanisms of AD and creating a novel cellular resource for the broad neuroscience community.