Modelling human disease in animals has significantly advanced our understanding of major diseases and ways of treating them. Mammalian model systems, like mice, continue to be the dominant model of choice, with 79% of experimental and breeding procedures using rats or mice in Great Britain in 2020. However, these traditional models can be bottlenecks in the research pipeline, delaying progress in areas where effective therapeutics are desperately needed. In a previous blog [1], I questioned whether a reliance on animal models, specifically mice, had delayed progress in dementia research. Now I will look at the alternatives and consider whether they can drive forward the breakthroughs we need in dementia research.
Animal models have historically been the basis for discoveries in biomedical research through elucidating disease mechanisms and developing treatments. Alzheimer’s disease (AD) is the most common brain disease which leads to dementia, and research using animal models have helped us to determine the pathological changes which occur in the brain in AD. However, this knowledge has failed to translate into effective treatments, with drugs developed to treat AD having a 99% overall failure rate in clinical trials, and those which have received approval have not proven to be particularly effective.
Mice are the most used mammalian model system in dementia research, and they have many advantages: they reproduce relatively quickly, they can be genetically modified, and being mammals, they do provide a degree of good translation to humans. However, mice do not get AD so researchers have largely relied on genetic modifications based on familial AD, which only accounts for around 3% of AD cases in humans. How comparable the disease onset and progression are to the more common sporadic form of AD is to be determined.
So what are the alternatives to using rodent mammalian models? There are three non-mammalian model organisms used in biomedical research which are making significant progress in dementia research and which I will discuss in this blog. The first are zebrafish which have emerged as a model for brain diseases which cause dementia, due to certain similarities in neuroanatomy and neurochemistry with humans, and because, like mice, they are amenable to genetic manipulation. Zebrafish have a high breeding rate and short lifespan which allows for high throughput screening of compounds. As zebrafish larvae are transparent, in vivo imaging allows for disease progression to be monitored on a cellular level. Cognitive and behavioural tests comparable to those used to assess cognitive function in rodents have also been developed, as zebrafish naturally exhibit memory, conditioned behavioural responses, and social behaviours which are all disrupted in AD. Zebrafish are therefore a promising alternative to rodent mammalian models.
There are three non-mammalian model organisms used in biomedical research which are making significant progress in dementia research – Zebra Fish, Drosophila (Fruit Fly) and C. elegans; a type of nematode, or roundworm
Drosophila, also known as the fruit fly, are another non-mammalian model progressing as an alternative to rodents in dementia research due to their short lifespan and being relative low cost. Drosophila have increasingly been applied in AD research as they express orthologues of amyloid precursor protein and secretase proteins, making them a useful model for understanding mechanisms of disease onset and progression. Being able to map disease pathology in the brain with cognitive changes is key to modelling disease that is translatable to humans. However, there is a lack of cognitive tests developed and validated for drosophila compared to rodents that go beyond general measures of central nervous system function. It is therefore difficult to consider drosophila as a complete alternative to rodent models, but perhaps they can be more effectively applied alongside other models, or at an early stage of the research pipeline before rodent models are used.
The final alternative making progress dementia research, is C. elegans; a type of nematode, or roundworm [2], which have been shown to be particularly effective at modelling the memory impairments typical in AD. Like zebrafish [3], they are amenable to genetic manipulation, have a relatively short lifespan, and are very cost-effective. C. elegans do not naturally express β-amyloid, one of the main characteristic pathological features of AD, so transgenic C. elegans have been developed to model this process to understand potential disease mechanisms. However, it is unclear to what extent this process mimics what happens in humans, or even a mammalian system, and as C. elegans do not have brains, it is unclear how much insight on neurodegenerative diseases they can provide beyond a molecular level. Despite issues around translatability, C. elegans can, as with the previous models discussed, be used not necessarily as a full replacement for rodents, but alongside them, ultimately reducing the need for rodent models particularly at various early stages where certain experiments can be done quicker and more cheaply with these alternatives.
Brain diseases which lead to dementia are complex and it is unlikely that we will ever have a single model organism which truly reflects how a disease like AD develops and progresses. The question now must be one of whether a combination of models that recapitulate aspects of the disease will be sufficient to help us understand the mechanisms driving the disease, and then develop targeted therapeutics that can either halt these mechanisms or prevent the disease process from being initiated altogether. C. elegans and drosophila are models which are cost-effective, with studies conducted relatively quickly, making them a useful tool for genetic and molecular research and high-throughput screening of new drug compounds. Then models such as zebrafish and mice can be used for assessment in more complex biological systems. Many biomedical research labs are already using this approach, so time will tell whether it will finally lead to significant breakthroughs in dementia research.
Dr Kamar Ameen-Ali
Author
Dr Kamar Ameen-Ali [4] is a Lecturer in Biomedical Science at Teesside University & Affiliate Researcher at Glasgow University. In addition to teaching, Kamar is exploring how neuroinflammation following traumatic brain injury contributes to the progression of neurodegenerative diseases that lead to dementia. Having first pursued a career as an NHS Psychologist, Kamar went back to University in Durham to look at rodent behavioural tasks to completed her PhD, and then worked as a regional Programme Manager for NC3Rs.