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beta (Aβ) peptide plaque formation and tau tangles. Progressive neuronal loss in the hippocampus and
[25]
other brain regions further leads to reduced levels of neurotransmitters .
PD, like AD, is a highly prevalent neurodegenerative disorder that has a multifactorial etiology and is most
often of idiopathic origin. Genetic and environmental factors contribute to the disorder that is primarily
characterized by the lack of the neurotransmitter dopamine, leading to bradykinesia and other motor
deficits in patients. Several PD-causing and PD-risk genes have been identified. Mutations in α-Synuclein
(SNCA), Parkin (PARK2), PTEN-induced kinase 1 (PINK1), Protein deglycase DJ-1 (DJ-1), and Leucine-
rich repeat kinase 2 (LRRK2) amongst others can cause the familial form of the disorder. On the cellular
level, PD is characterized by mitochondrial dysfunction, altered protein degradation pathways, and
increased neuroinflammation leading to synaptic dysfunction and neuronal loss in the substantia nigra pars
[26]
compacta .
HD is a monogenetic ND caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT), which
translates to a poly-glutamine tract in the huntingtin protein (HTT) [27,28] . HD commonly manifests in
adulthood, with CAG expansions in a range of 36 to 60 CAG repeats . More than 60 CAG repeats are
[29]
associated with juvenile HD, leading to symptom onset before the age of 20 years . The neuropathological
[30]
hallmarks of HD are extensive cell loss in the striatum and HTT aggregates localized in the neuropil,
perikarya, and nucleus [31-33] . The clinical manifestations include motor deficits, cognitive impairment, and
psychiatric disturbances .
[34]

This review provides an overview of rat models that have been generated to study the above-mentioned
NDs, AD, PD, and HD. Neuropathological characteristics and behavioral phenotypes of well-characterized
genetic models are summarized and stand in contrast to phenotypic/aspect-replicating rat models that are
historically and currently more commonly used in biomedical research. We aim to highlight the advantages
both types of rat models offer in terms of readouts and study design opportunities to improve translatability
to human treatment.

GENETIC RAT MODELS TO STUDY AD, PD, AND HD
Neuropathological phenotypes
Neurodegenerative diseases represent a large group of neurological disorders with progressive loss of
particular subsets of neurons. The most common NDs are Alzheimer’s disease (AD) and Parkinson’s
disease (PD); and as a monogenic disease, Huntington’s disease (HD), is well-studied. In addition to the
progressive and selective neuronal cell loss, the second central characteristic of NDs is the presence of
protein aggregates composed of misfolded proteins, specifically, the N-terminal fragment of mutant
huntingtin in HD, Aβ peptide and hyperphosphorylated tau in AD, and α-synuclein (α-syn) in PD. The role
of protein aggregates in NDs, whether neurotoxic or neuroprotective, is still a matter of debate since the
distribution of protein aggregates does not reliably match the patterns of neuronal loss in different
diseases . Nevertheless, due to its commonality among NDs and its dependency on a specific molecular
[35]
cascade (i.e., misfolding, oligomerization, and fibrillization), protein aggregate formation remains an
important aspect of ND research. Thus, animal models that recapitulate the disease’s characteristic protein
aggregation pathologies can make great contributions to understanding the disease mechanisms and aid in
the development of therapeutic strategies. For genetically modified animal models of NDs, the presence, as
well as the regional and subcellular location of protein aggregates, depends on the genetic construct’s
promoter, protein expression levels, and genetic background of the animal. Mouse models have closely
recapitulated the features of human NDs and provided essential insight into neuropathology. However, no
single animal model can mimic all aspects of human diseases, not even all mouse models, collectively. Rats