Microscopy characterization of a novel tau model of Alzheimer's Disease in monkeys

University Of California At Davis, Davis CA

Investigators

Abstract

PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease (AD) is a devastating condition that affects more than 6 million Americans, with a total annual cost >$300 billion estimated in 2022. Currently, there are few treatments to counteract or slow the progression of AD, with promising findings in mice generally failing to translate into successful therapies for patients. Monkey models may provide a more powerful translational model. This work proposes to characterize fully a monkey model of AD tau pathology by performing microscopic analyses on the brains of rhesus macaques I am currently behaviorally testing to characterize tau-based cognitive decline (R24AG073138). Previous work has targeted the highly vulnerable entorhinal cortex (ERC) for unilateral infusions of an adeno-associated virus (AAV) expressing a double tau mutation known to cause tau-related dementia in humans (P301L/S320F) and characterized neuropathology at 1.5, 3, and 6 months after viral infusion. This causes extensive and progressive neuroinflammation and tau-based neuropathology, including neurofibrillary tangles, in ERC and in hippocampal and neocortical targets of ERC. PET imaging in these monkeys displays robust tau expression. Biomarkers for neurodegeneration are elevated in serum and CSF relative to baseline levels. The progressive time course relative to the time of vector infusion is a great strength in terms of using this model for therapeutic development. These early studies demonstrated 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. The successful characterization of this model with cutting-edge scientific methods will result in a multi-faceted and highly validated rhesus monkey model of the tau-based degenerative phase of AD with unprecedented translational power for efficiently developing and testing therapeutics throughout the pathological process. To meet this critical need, this project pursues two Specific Aims: 1) This project performs comprehensive microscopic studies to determine the regional and laminar patterns of tau-based neuropathology and extent of neuronal loss within the ERC and hippocampus 12 months after AAV injection into ERC, as well as more distal neocortical sites. This project correlates the tau-based pathology, including neuronal death, with the behavioral data I am currently collecting from the same animals. 2) This project performs comprehensive microscopic studies to determine the regional and laminar patterns of synaptic and neuronal health within the ERC and hippocampus, as well as more distal neocortical sites. This project correlates synaptic and neuronal health, which is closely related to neuronal functionality, with the tau-based pathology described in Aim 1, as well as the behavioral data I am currently collecting. A particularly novel aspect of this project is the utilization of immediate and early genes (IEGs) to study the health of neural circuits in use by the animal when exposed to a novel environment immediately before perfusion. All microscopic analyses and behavioral correlations will be highly quantitative and rigorous, facilitating therapeutic development and correlation across prior datasets.