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Page 2 of 11 Zhang et al. Ageing Neur Dis 2022;2:16 https://dx.doi.org/10.20517/and.2022.15

INTRODUCTION
Neurodegenerative diseases (NDDs) are associated with progressive neuron losses, most of which are linked
[1]
with genetic disorders . At present, neurological disorders are considered as one of the major causes of
mortality and disability worldwide . Unfortunately, many NDDs are late-onset and hard to detect in the
[2]
early stage; for instance, Parkinson’s disease (PD) and Alzheimer’s disease (AD) have high morbidity in
elderly patients, while amyotrophic lateral sclerosis (ALS) does not exhibit clear symptoms at the early stage
of the disease. Moreover, due to the irreversibility of neuronal death, no effective therapeutic approaches are
available at present. Therefore, a thorough investigation of these diseases is essential for the development of
disease-specific and effective prognostic, diagnostic, and therapeutic strategies. Model organisms are
essential platforms for the above research; cell lines and animal models are frequently used. Although cell
models can be used for the investigation of pathological pathways and molecular mechanisms of disease
[4]
[3]
pathogenesis , due to the limitation in modeling organogenesis and human physiology , they cannot
mimic histological, morphological, and behavioral changes in human diseases. Therefore, animal disease
models that partially recapitulate the aspects of human diseases are essential. Additionally, animal models
have irreplaceable value in preclinical tests; they are also important for the development of prognostic and
therapeutic strategies.

In comparison with non-mammalian animals such as zebrafish and Drosophila melanogaster, mammalian
models have greater similarities to humans in genetics, metabolism, and physiology and can therefore
[5,6]
mimic some of the biological and clinical features of human disease . In practical research, large animal
models are often used because of the biological characteristics of these animals for modeling human
[7]
NDDs . With the development of genome editing tools and somatic cell nuclear transfer (SCNT)
techniques, genetically modified large animal models can be effectively produced, which can promote the
utilization of these models . Unfortunately, maintenance costs, space requirements, and ethical standards
[8]
are still problems for the use of large animal models in biomedical research. Compared with large animal
models, rodents have a small body size, low maintenance cost, and can be easily handled, making them cost-
efficient models. Moreover, rodents have a relatively high genetic identity and physiological similarity to
humans, and genetic modification capabilities can facilitate the modeling of genetic disorders . Therefore,
[9]
currently, rodents are the main experimental animal for biomedical research and disease modeling. From
1950 to 2010, approximately 80% of animal-based biomedical studies were performed on rodents (59% on
[10]
mice and 18% on rats) .

Rodents have been applied in modeling many neurological diseases and have adequate precision in
mimicking the pathology and physiology in some cases. However, due to factors such as lifespan, genetic
differences from humans, and small body size, rodent models have some limitations in studying neuronal
disorders . For example, they cannot replicate the exact pathological hallmarks in some human diseases
[9]
because of physiological and genetic differences. PD mouse models (α-synuclein transgene or knockout of
LRRK2, PRKN, and PINK1) do not show degeneration of nigrostriatal dopaminergic neurons and striatal
[11]
[11]
neurons remain viable, which is different from the pathological features in human disease . The absence of
intranuclear inclusion body formation in neuronal cells of ALS mice overexpressing mutant hSODl is
inconsistent with the phenotype of human ALS disease. Thus, finding an alternative animal species for
modeling is needed to produce better models for diseases that cannot be recapitulated in mice.

Rabbits are docile and easy to handle; their short reproductive cycle and high reproductive performance can
guarantee an abundant sample size for experiments; and the efficiency of model production and the low
demand for rearing and surgical operation equipment make rabbits easy to maintain and handle .
[12]
Moreover, rabbits have an intermediate lifespan (longer than rodents but shorter than large animals such as