For Alzheimer's studies, animal model selection is everything

The humble lab mouse is an essential research tool, helping researchers understand the biological processes that underpin disease development and progression. The ability to observe disease pathology in a complex living system is tough to replicate in vitro, says Andrea Leonardi, scientific program manager at Taconic Biosciences, a global provider of genetically engineered rodent models and services.

“While bioinformatic and in vitro systems are useful for validation studies, it’s difficult to accurately reproduce human disease pathology without an animal model where you have cells interacting with each other, circulating factors like hormones and, especially in Alzheimer’s models, the effects of ageing,” Leonardi says.

But finding the right model for a study can be challenging, particularly when it comes to complex neurodegenerative conditions.

“There are currently no animal models that fully recapitulate Alzheimer’s disease as we see it in humans,” says Kamar Ameen-Ali, a neuroscientist at Teesside University in the United Kingdom. “Alzheimer’s mouse models typically rely on genetic modifications that mimic certain aspects of the disease.”

The rising incidence of neurodegenerative conditions is putting pressure on researchers to better understand them, and to develop more translational models to help that process. The first transgenic mouse used to study Alzheimer’s disease was created in 1995. Now, there are more than 200 models, and the key for any study using preclinical models is to narrow the options down.

“The model used by a researcher needs to be selected based on its characteristics and whether it can be a useful tool for answering their research question,” says Ameen-Ali. Given the varied, interrelated mechanisms involved in neurodegenerative disease, it is critical to be able to study one mechanism or hypothesis at a time in a translatable model, says Moriah Jacobson, a behavioural neuropharmacologist and Taconic field applications scientist.

Imaging the Alzheimer’s brain

With that goal in mind, Taconic partnered with LifeCanvas Technologies, a biotech specializing in whole-organ tissue-clearing, imaging and analysis. LifeCanvas used Taconic mouse models to generate 3D whole-brain images displaying the amyloid plaques and other pathological markers characteristic of Alzheimer’s disease. Such images provide an ultra-detailed view of disease pathology over time, including spatial context, that can be used to derive critical information about plaque deposition and associated neuroinflammation.

Insights gleaned from this unprecedented perspective could ultimately improve understanding of the disease’s progression and guide new therapy development. “This is going to be incredibly important for determining how to arrest or slow the progression of Alzheimer’s-related neurodegeneration,” says Adam Hall, head of scientific affairs at LifeCanvas.

Precise animal model selection proved vital for this project, which combined complex 3D imaging technology and analysis via machine learning. “Taconic has really robust models for Alzheimer’s disease,” says Hall. “We needed a large cohort of reproducible, established animal models to generate sufficient image data to improve our machine-learning algorithms, so we could develop analysis capabilities for plaque mapping and quantification.”

Brain samples from Taconic’s ARTE10 and APPSWE mouse models were the right match. These models have a mutated form of the human gene for amyloid precursor protein, which increases β-amyloid production. When pieces of β-amyloid clump together in the brain, they form the characteristic plaques (at about seven months in the APPSWE and four months for the more aggressive ARTE10 model). Image data from the ARTE10 and APPSWE brains were registered with the Allen Brain Atlas and run through a machine learning algorithm for plaque detection and quantification.

“This is a great case study of how collaboration can advance research on complex neurological conditions,” says Jacobson. “Working with LifeCanvas, we’re characterizing models in ways that have never been done before. They are validating and optimizing their protocols while we get new data on models of neurodegenerative disease, which is key to accelerating research.”

The next step is to acquire even higher-resolution data that highlight not only where the plaques are, but also how they are invaded by microglia and astrocytes. The teams also aim to tag drugs with fluorescent molecules to see how they interact with damaged sites in the brain. Future collaborations could extend to other diseases like Parkinson’s and amyotrophic lateral sclerosis (ALS).

Alzheimer’s studies: developing animal models the right way

Developing animal models for Alzheimer’s research is itself a complex field. Some models represent the inherited form of the disease, while others reproduce the sporadic form. Some models are better for studying plaque development, and others are designed for investigating neurofibrillary tangles.

Ageing plays an important role in Alzheimer’s progression. Certain mouse models can manifest disease pathology as juveniles, which some researchers prefer because they can start studies sooner. But studies in such early onset cases may not translate into the predominant late-onset forms of the disease.

Older mice, however, create their own challenges, as Leonardi explains. Populations naturally decline over time, so breeding plans must consider expected survival rates. Ageing mice may become more aggressive and develop tremors, impaired motor skills and difficulty accessing food. To minimize the impact of such obstacles, animal model providers can adjust cage density or provide enrichment, but they must be careful to avoid interfering with disease progression.

What’s more, animals need to be bred using globally harmonized procedures and health standards to ensure they are genetically identical and give reproducible results, even if they are bred at different locations and times.

Not all research groups can take on these challenges, which is where a specialist partner like Taconic comes into play. “If an investigator can’t dedicate the time, staff resources, or vivarium space to breed and manage a colony for two to four years, we step in and manage that portion for them,” says Leonardi.

Sometimes, off-the-shelf models can’t fulfil a researcher’s needs and a new model needs to be designed. This comes with its own set of challenges, depending on the genetic modification methodology used and the behavioural phenotype desired. Humanized genes might be expressed differently when randomly inserted into mouse embryos, as in transgenic models. Embryonic stem cell modification can be more targeted, efficient and versatile, but takes longer than approaches such as CRISPR/Cas9 gene editing. Scientists in Taconic’s Custom Model Generation group can help identify the best genetic modification technique to suit the study objective and gene of interest.

Whatever the field of preclinical study, engaging with the right partner can bring important benefits to research teams, whether they’re seeking new models, advice on off-the-shelf options, or to collaborate on breeding plans. “As the investigator’s partner, Taconic is there every step of the way,” says Jacobson. “We ensure they get a relevant, translational model that enables them to achieve their vital research objective.”