Afonso C. Silva, Ph.D. - US grants

PROJECT TITLE: Development and Validation of a Marmoset Model of Late-Onset Alzheimer?s Disease Based on Tau Seeding PROJECT SUMMARY/ABSTRACT: Alzheimer?s disease (AD), the most common cause of dementia, currently afflicts 5.8 million Americans. By 2050, the number of people with AD could reach nearly 14 million. Histopathologically, AD is characterized by the formation of extracellular aggregates (plaques) of beta-amyloid (A?) protein fragments and intracellular aggregates (neurofibrillary tangles, NFTs) of a hyperphosphorylated form of the microtubule-associated protein tau (MAPT). Increasing evidence indicates that both A? plaques and NFTs begin to accumulate in the brain decades before symptoms emerge. The long delay between A? and tau manifestation and the onset of memory loss and cognitive decline in AD makes it difficult to properly model AD using short-lived animal models, such as mice. As age and genetic variation are two of the most significant risk factors for AD, there is a critical need to develop improved animal models of AD that incorporate genetic variability, aging, and higher- order cognitive processes that better align with humans. The common marmoset (Callithrix jacchus) is a small non-human primate (NHP) ideally poised to fill this need. They display social and cognitive behaviors that are more similar to those of humans. Marmosets live on average 12-13 years and are considered aged at eight years. A? plaques and hyperphosphorylated tau occur naturally in the brain of aging marmosets. Developing strategies to accelerate the onset of cognitive decline related to the presence of pathological hallmarks of AD in marmosets would lead to establishing an NHP model with improved translational potential relative to rodent models. The overall goal of this proposal is to develop and validate an induced marmoset model of late-onset AD. Converging clinical data indicates that the severity of cognitive impairment in sporadic AD correlates best with the burden of NFTs. We hypothesize that injecting the brain of aging marmosets with tau will seed the formation and propagation of NFTs and accelerate the emergence of impairments in a spectrum of AD-related sensory, motor, cognitive and non-cognitive phenotypes associated with disease progression. We will test this hypothesis in two aims. In Aim 1, we will use neuronal cell cultures derived from aging marmosets to quantify the spontaneous presence of AD-related pathology in vitro and evaluate the efficacy of tau seeding strategies in accelerating the development of NFTs and promoting neurodegeneration and cell death. In Aim 2, we will seed the brains of aging marmosets with tau, and perform a comprehensive longitudinal evaluation of functional, behavioral, and clinical biomarkers of AD in the tau-seeded marmosets. This work will lead to the establishment of a validated NHP model of late-onset AD that will be invaluable in translational research to elucidate the pathogenic mechanisms of AD and contribute to developing new therapeutics for AD.