Sunday, May 18, 2025
5/18/2025
Frontotemporal dementia in rhesus macaques - ABSTRACT Frontotemporal dementia (FTD) is the most frequent dementia in patients under 60 years old. Mutations in MAPT (the gene encoding for the Tau protein), including the autosomal dominant R406W missense point mutation, have been linked to FTD. Current evidence supports the concept that FTD neurodegeneration starts decades before symptom onset, yet genetic FTD studies in young adults or minors are seldomly done, due to the challenges of disclosing genetic condition and the burden of long-term testing. Defining when the pathological processes begin will be critical to administer neuroprotective therapies before substantial neuronal loss and, therefore, to prevent FTD onset. At the Wisconsin National Primate Research Center (WNPRC) we currently have 6 rhesus macaque carriers of an exact replica of the human MAPT R406W mutation. They are 3 adults (19, 6 & 7 yrs.), a young adult (4 yrs.), a juvenile (2 yrs.) and an infant (0.6 yrs.); 3 more offspring are due October/November 2023. These nonhuman primate (NHP) carriers provide a unique opportunity to longitudinally and systematically assess biomarkers of FTD-tau. The overarching goal of this proposal is to identify the earliest biomarkers of FTD and their timeline of onset across the lifespan of MAPT R406W rhesus, aiming to inform clinical translation. Based on our preliminary findings, we hypothesize that prodromal FTD-tau begins during the transition period of sexual maturation from juvenile to young adult. To test this hypothesis, we propose three Specific Aims: 1) To characterize across the lifespan the onset of FTD-like cognitive, mood and motor behaviors of rhesus MAPT R406W mutation carriers; 2) To identify early imaging predictors of brain neurodegeneration in rhesus MAPT R406W mutation carriers. 3) To assay CSF and blood fluid biomarkers of FTD-tau linked to neurodegeneration in rhesus MAPT R406W mutation carriers and assess their temporal relationship with imaging and behavioral biomarkers. We will access databases at WNPRC for NHP normative rhesus data. To facilitate harmonization between old and new datasets, additional MRI and biofluids assays will be collected from animals of the WNPRC colony. We will maximize the translational value of the NHP resource, by comparing the results to human datasets available through the Tau consortium. This rhesus study is timely due to the availability of the MAPT R406W monkeys generated by the R61/R33 NS115103 award, and fulfills a gap in clinical research. The NHP results will be enriched in the future by postmortem analyses, as more rhesus carriers become available. The findings generated by this rhesus project will inform on the impact of the tau mutation in early neurodevelopmental stages and assist in the design of future neuroprotective preclinical and clinical studies.
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