Modeling Frontotemporal Dementia in Rhesus Macaques

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ABSTRACT Frontotemporal dementia (FTD) with or without parkinsonism, is an Alzheimer’s disease related dementia (ADRD) that has been linked to sporadic and familial mutations in the MAPT gene, including the autosomal dominant R406W missense point mutation. Patients with FTD MAPT R406W present progressive memory loss, and late-onset of parkinsonism, personality changes, and/or language deficits. Typical pathological findings include abnormal intraneuronal accumulation of phosphorylated tau filaments (tauopathy), frontotemporal atrophy, neuronal loss, and gliosis. At the Wisconsin National Primate Research Center (WNPRC) in collaboration with Baylor College of Medicine, a rhesus monkey was identified as a carrier of the MAPT R406W mutation, identical to human patients. Progress in the development of biomarkers and treatments for FTD and other dementias has been hampered by the lack of faithful animal models of the disorder. Nonhuman primates (NHPs), in particular rhesus macaques, are an ideal species to study dementias and related neurodegeneration, due to the complexity of their behavior and neuroanatomy. In the R61 phase of this application we propose to phenotype the MAPT R406 carriers of this family and to identify additional MAPT R406W mutation carriers. The rhesus will be evaluated with a battery of age-appropriate behavioral tests (cognitive, mood and motor), MRI (for neuroanatomical and volumetric analysis) and F18-MK6240 PET (to visualize tau accumulation) and compared to age- and sex- matched controls. These animals will be the founders of a breeding colony of MAPT R406W carriers. During the R33 phase we will aim to create a MAPT R406W rhesus colony resource, by breeding the mutated rhesus and generating induced pluripotent stem cells (iPSCs) from the carriers’ fibroblasts. The offspring will be genotyped and neurobehaviorally evaluated. The iPSCs will be a platform to study the effects of ADRD alleles on in vitro neural differentiation. The overarching goal of this project is to generate an NHP resource for the ADRD research community. A well characterized NHP model of genetic FTD, supported by in vivo behavioral and imaging outcome measures and associated iPSC lines, will help understand the pathological mechanisms of the disease, which could lead to the identification of biomarkers and therapeutic targets. We have assembled a strong team of investigators across different disciplines focused on translational neuroscience and neurodegenerative diseases, human and nonhuman primate genetics, stem cells, and, most importantly, experts devoted to nonhuman primate breeding and care.