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Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19 Page 17 of 29

Over the past decade, improvements in biomarker identification and quantification and improved
preclinical study design have been implemented to increase translatability to human studies. Incorporating
such study design, a genetic rat model has been used in a preclinical study with improved longitudinal
assessment of biomarkers to improve translatability. Continuous CSF and plasma collection for
measurement of Aβ and neurofilament light chain in combination with PET and MRI imaging have been
[299]
used to evaluate an anti-amyloid therapy in McGill-R-Thy1-APP transgenic rats .
Phenotypic rat models of Parkinson’s disease
Due to the multifactorial etiology of PD and most cases being of idiopathic origin, neurotoxin and lesion
models are mostly relied on for preclinical Parkinson’s research. The main neuropathological feature of the
disease, the loss of dopaminergic neurons in the substantia nigra can be modeled through the injection of
hydroxydopamine (6-OHDA) in most studies into the substantia nigra pars compacta or in the medial
[300]
forebrain bundle . Next to cell loss, lesioned rats show motoric deficits that are correlated to the degree of
dopaminergic neuron loss, oxidative stress, and neuroinflammation [280,301] . Test paradigms have been
developed to assess motor deficits, resembling akinesia, fine motor impairment, and showing rotational
[301]
response to dopaminomimetic agents when extensive unilateral lesioning is produced . While the lesions
produced resemble cell loss in humans, unilateral lesions are mostly used in experimental settings, inducing
cell loss in one hemisphere only. These lesions are mostly produced in rats, as mice are more prone to
weight loss and post-lesion mortality which can be circumvented by modification of the injection sites and
improved post-surgical surveillance [302-304] .

Another neurotoxin model is the MPTP mouse model. In contrast to 6-OHDA, which does not cross the
blood-brain barrier, MPTP can be administered systemically, but shows larger variation in neuronal loss in
the substantia nigra and the motor phenotype is not fully equivalent to PD patients . MPTP has been
[305]
mainly used to mimic PD in mice in many different treatment studies, as rats are highly resistant to MPTP.
One rat model of unilateral brain infusion with MPP+ has been developed, which shows progressive loss of
dopaminergic neurons .
[306]
Phenotypic rat models of Huntington’s disease
Only few preclinical studies have been performed in transgenic rat models of HD despite the monogenetic
etiology of HD [111,307] . To a greater extent, neurotoxin models are used to model histopathological
characteristics of the disease or mechanism of neuronal demise to test preventive therapies or therapies
aiming at restoring functionality. The two most commonly used substances are quinolinic acid (QA) and 3-
nitropropionic acid (3-NP). QA is an excitotoxin, binding to the N-methyl-d-aspartate (NMDA) receptor
and more strongly affecting neurons within the hippocampus, striatum, and neocortex. It can induce
different neuron and glia-damaging effects, also dependent on the dosage . The lesions produced are
[308]
structurally similar to HD characteristic lesions within the striatum and limited to the area around the
injection site [283,309] . Impairment of paw use can be assessed in cylinder test, altered grooming behavior has
been described, and learning and motoric abilities are altered in this model [310-312] .

Systemic injection with 3-NP, an irreversible inhibitor of succinate dehydrogenase in the mitochondria,
leads to striatal neuronal degeneration, as well. Rats are more sensitive to 3-NP than mice and develop
lesions and behavioral alterations [284,313] . The lesions produced by 3-NP are more severe and cause a
phenotype that includes learning impairment, reduced grip strength, and balance deficits that are more
[310]
severe than in the QA model .