Characterization and Validation of Two Recently Created Sheep Models of Alzheimer’s Disease in Preparation for Use as a Preclinical Pharmaceutical Testing Model

2024

There has been rapid recent progress in understanding the molecular pathogenesis of Alzheimer’s disease (AD). This has culminated in the confirmation that injected antibodies targeting sticky protein fragments called amyloids can slow the progress of the disease. Although amyloid may not be the only viable treatment target, these results confirm the decades-old hypothesis that amyloid is central to the disease process. Whilst these treatments are undoubtedly a breakthrough, the antibody therapy approach is not perfect. It does not prevent the disease, is expensive, and has associated side effects, some serious. One of the challenges when developing treatments is finding a model system to test them in. Good model systems increase the likelihood that the treatments will be successful in human clinical trials, which are logistically challenging, long, and expensive. To this end, our group and international collaborators have made two sheep models of AD. We recognized the deficiencies in the heavily used rodent models, which led us to make new animal models that could accurately capture the full range of AD pathology. These animals have been engineered to develop AD in a way that is identical to the natural disease process. Sheep naturally develop the brain changes seen in AD and this is because the genes responsible are very similar to humans. To accelerate this process, we have altered a single gene in each model to create the same mutation found in humans who develop early-onset forms of AD. These two human patient groups show early changes in amyloid production that can be detected in blood and cerebrospinal fluid. Both of our sheep models show blood changes, confirming that they are indeed models of AD; however, the number of sheep was relatively small. Our aim is to undertake robust measurements of AD progression on a larger number of animals from both lines to establish a baseline for the use of these models for pharmaceutical testing. We will also produce and test the disease development rate in a cohort of animals carrying both mutations, aiming to accelerate the disease process and facilitate more rapid treatment testing. Lastly, we also plan to test what happens to disease progression by decreasing the expression of a key gene involved in amyloid production as a potential therapeutic avenue. We can undertake both these investigations by simply cross-breeding with existing sheep. Once characterized, these sheep will be made available for pharmaceutical preclinical testing and to the wider scientific community to study AD.

2023

One of the challenges when developing treatments is finding a model system to test them in. Good model systems increase the likelihood that the treatments will be successful in human clinical trials, which are logistically challenging, long and expensive. To this end, our group and international collaborators have made two sheep models of Alzheimer’s disease (AD). These animals have been engineered to develop AD in a way that is identical to the natural disease process. Sheep naturally develop the brain changes seen in AD, because the genes responsible are very similar to humans. To accelerate this process, we have altered a single gene in each model to create the same mutation found in humans who develop early-onset forms of AD. Both of our sheep models show the expected blood changes, confirming that they are indeed models of AD. Our aim is to undertake robust measurements of AD progression on a larger number of animals from both lines to establish a baseline for the use of these models for pharmaceutical testing. We also will produce a cohort of animals carrying both mutations aiming to accelerate the disease process for more rapid treatment testing. Lastly, we also plan to test what happens to disease progression by decreasing the expression of a key gene involved in amyloid beta production, as a potential therapeutic avenue. Once characterized, these sheep will be made available for pharmaceutical preclinical testing and to the wider scientific community for the study of AD.