Project Details
Description
Alzheimer’s disease (AD) is a devastating condition that affects more than 5 million Americans,
with a total annual cost of more than $300 billion predicted in 2020. Currently there are no effective
treatments to counteract or slow the progression of AD, with promising findings in rodents failing
to translate into successful therapies for patients. Monkey models may provide a more powerful
translational model. The goal of this proposal is to characterize a monkey model of tau pathology
in AD. This is responsive to RFA-AG-21-003 requesting proposals that target the “development,
characterization, and validation of suitable new or unconventional mammalian non-murine models
of AD that may represent improved translational potential by better replicating pathological
features of the disease”. With respect to nonhuman primate (NHP) models of AD, the RFA states
explicitly that “NHP have a very high translational value because of their close relationship to
humans in terms of phylogeny, genetics, physiology, cognition, emotion, and social behavior”. In
this proposal we describe initial findings in a tau-based monkey model of AD and propose a
program to fully develop and validate the model by three PIs who have decades of experience on
aging and neurodegeneration in NHP models. We have targeted the highly vulnerable entorhinal
cortex (ERC) for unilateral infusions of an adeno-associated virus expressing a double tau
mutation known to cause tau-related dementia in humans (AAV-P301L/S320F) and characterized
neuropathology at 3 and 6 months after viral injection in NHPs. This causes extensive and
progressive neuroinflammation and tau-based neuropathology, including end-stage neurofibrillary
tangles, in ERC and in hippocampal and neocortical targets of ERC. Preliminary PET imaging in
these monkeys displays robust phospho-tau accumulation in the hippocampus. The progressive
time course relative to the time of vector injection is a great strength in terms of using this model
for therapeutic development. These early studies demonstrate the potential for this model to
replicate pathological features of AD in the monkey brain and to capture aspects of pathology that
have not been well-modeled in rodents. We propose to do a full, rigorous characterization of this
model, including long-term behavioral assessment, in vivo imaging, fluid biomarker assessment,
and microscopic analyses. Full characterization of this model, will provide a platform to test
therapeutic agents at different points in the disease process.
Status | Active |
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Effective start/end date | 1/09/21 → 31/05/23 |
Funding
- National Institute on Aging: $1,296,257.00
- National Institute on Aging: $1,295,793.00
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