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Page 2 of 4 Li. Ageing Neur Dis 2023;3:17 https://dx.doi.org/10.20517/and.2023.24

Novati et al. discussed the use of rat models in investigating Alzheimer’s, Parkinson’s, and Huntington’s
[1]
diseases . Genetically modified rat models have been employed for studying human diseases over the past
20 years and have proven to be valuable tools for investigating NDs. Rats offer several advantages over mice,
such as genetic similarities to humans and larger body size, which allow for a more precise evaluation of
therapeutic effects. Numerous behavioral tests and electrophysiological assays have been developed for rats,
enabling a more robust assessment of behavioral and cellular phenotypes in these models. Additionally, rats
exhibit a more complex behavioral repertoire than mice, allowing for a more sophisticated extrapolation to
the human condition. While rats are less commonly used in biomedical studies compared to mice, they fill a
gap when genetic mouse models fail to replicate certain aspects of diseases and can provide additional
insights into disease mechanisms. However, similar to mouse models, rats also face challenges in
recapitulating the overt and selective neurodegeneration observed in patient brains with NDs.

Zhang et al. introduced rabbit models, with a focus on genetically modified rabbits, for investigating human
[2]
diseases . Rabbits are docile and easy to handle, and their short reproductive cycle and high reproductive
performance ensure a sufficient sample size for experiments. Additionally, the efficiency of model
production and the low demand for rearing and surgical operation equipment make rabbits easy to
maintain and handle. Moreover, rabbits have an intermediate lifespan, longer than rodents but shorter than
large animals such as non-human primates. Compared with rodents, rabbits are phylogenetically closer to
humans and exhibit greater similarity in brain development, suggesting that they may provide better
precision in disease modeling. With the development of targeted genome editing tools, it has become
feasible to produce targeted genome-edited rabbit models for human neuronal disorders. To date, more
than 50 genome-edited rabbits have been constructed. However, there are very few rabbit models
established for modeling NDs, and the evaluation criteria for rabbit neurodegenerative disease models are
not well established. Despite these limitations, rabbits could serve as an alternative animal model to
investigate whether they can accurately replicate important neurodegenerative features.

Li et al. described the use of pig models for investigating neurodegenerative diseases . Pigs possess a brain
[3]
structure and function that is very similar to humans, making them an excellent choice for studying
important brain diseases. Unlike small animals, pigs have sulci and gyri, and their brain volume is
comparable to that of humans. These characteristics offer distinct advantages in studying NDs.
Additionally, pigs have a short reproductive cycle (5 months-6 months of sexual maturity) and can produce
multiple litters (an average of 7 piglets-8 piglets), making them more advantageous than non-human
primates. Moreover, pigs can be ethically used for translational research.

The relatively fast breeding and reproduction of pigs allow for a sufficient number of animals to evaluate the
therapeutic effects of drugs and other interventions. Another advantage of using pigs is the availability of
somatic nuclear transfer technology, which enables genetic modification of endogenous pig genes to create
knock-in or knock-out pig models. An excellent example is the establishment of a Huntington disease (HD)
knock-in pig model using a combination of CRISPR/Cas9 and somatic nuclear transfer. This pig model
exhibits behavioral phenotypes and selective neurodegeneration similar to HD patients, providing the first
evidence that disease genes expressed at the endogenous level can lead to neurodegeneration in large
animals (Yan et al., 2018) . Therefore, genetically modified pig models will play an increasingly important
[4]
role in the study of age-dependent neurological diseases in the future.

Non-human primates are closer to humans in terms of genomic regulation, aging process, metabolism, and
physiology than other species. Monkeys provide a more accurate genomic context for investigating
molecular pathogenesis. For instance, genome-wide association studies have identified the APOE ε4 allele as