Over 5.7 million Americans are currently living with AD, which is the most common cause of dementia. The societal cost for AD management exceeds $250 billion (Alzheimer?s Association, 2018). Despite these alarming statistics, AD initiation and progression continues to be poorly understood, and recent clinical trials have not led to promising therapeutic strategies. There has been a sustained effort to model AD in rodents, however the translational knowledge gained from these models has been unsatisfactory; many promising drugs demonstrating success in rodent models have not shown efficacy in clinical trials that have cost hundreds of millions of dollars. These disappointments have led to a reevaluation of these small-animal models, whose brains intrinsically differ from those of humans in terms of anatomy, physiology, endocrinology, and behavioral repertoire. It is our contention that powerful nonhuman primate (NHP) models of AD are essential to moving the field forward. In our past work, we have not only shown that these models are feasible but also that they can provide data of significant relevance to understanding and modeling human AD. We have been developing an A? oligomer-based model of the earliest synaptic phase of AD, and through previous administrative supplement funding, our group is developing a tau-based monkey model of the degenerative phase of AD. To establish our current monkey tau model, we are using adeno-associated viral vector (AAV) constructs with multiple tau mutations that form pathologic tau aggregates in human and that form neurofibrillary tangles (NFTs) in rodents. Our overall objective with this model is to produce two key phases of tauopathy linked to AD: 1) the transport of tau aggregates along pathways to vulnerable regions, and 2) synaptic alterations and/or the formation of NFTs throughout linked cortical regions. Under the auspices of our previously awarded Supplement, we have pursued the tau mutant-based model and successfully injected the mutant tau constructs into 10 rhesus monkeys that are scheduled to be sacrificed at 3 months (April, 2019) and 6 months (July, 2019) post injection. However, due to limited funds, our current and planned studies under the existing Supplement have employed only microscopic and histologic endpoints. In this proposal, we will perform the logical next step: an in vivo imaging-based characterization of this model. The availability of validated in vivo imaging metrics would enable longitudinal studies in the same animals across developmental and aging time points, thus significantly increasing study effect size and facilitating the direct comparison to human studies, facilitating the pursuit of new lines of investigation regarding AD progression and therapy with increased translational power. We are confident that such models can be developed and that their imaging characterization will provide an extraordinary resource for the development and testing of therapeutics aimed at prevention and treatment of AD.
Alzheimer?s Disease (AD) remains one of the most devastating and challenging societal health concerns that we face. The studies described in this application will characterize the temporal and spatial progression of tau-based pathology in a rhesus monkey model of AD using in vivo imaging techniques in parallel with quantitative microscopic analyses. Such studies will improve our understanding of early degenerative processes in AD and provide a powerful translational platform for testing new therapies designed to prevent or modulate the degenerative cascade of AD.
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