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and mice are closely related species, but still have genetic and physiological differences, such as the distinct
expression pattern and localization of certain protein isoforms. These diversities lead to some variance
between both species in resembling human pathological processes, making rat models a meaningful
complement to mouse models. This section discusses the commonly used genetic rat models for AD, PD,
and HD [Table 1], and describes to what extent they recapitulate the characteristic protein aggregate
pathology.

Neuropathological phenotypes in genetic rat models of Alzheimer’s disease: APP NL-G-F knock-in, TgF344-AD
and McGill-R-Thy1-APP transgenic rats
Amyloid plaques containing Aβ peptide and neurofibrillary tangles (NFTs) consisting of
hyperphosphorylated microtubule-associated protein (tau) make up the typical protein aggregate forms in
AD. While some studies suggested that tangles may precede plaques, it is commonly accepted that the
[49]
amyloid plaques are formed first and trigger tau agglomeration (see review ). Nevertheless, both amyloid
plaque and tau tangles are characteristic features of AD. The development of amyloid plaques appears to be
dependent on the initial accumulation of Aβ, which is derived from amyloid beta precursor protein (APP)
through sequential proteolytic cleavage by β and γ-secretase. Mutations in APP close to the main APP
cleavage site and in the catalytic subunit of γ-secretase presenilin (PSEN) are major genetic causes of familial
AD [50,51] . Ultimately, overexpression of APP with a combination of multiple mutations has been used to
generate APP transgenic models [52-54] , while double transgenic models expressing mutant APP and mutant
[36]
PSEN represent APP/PSEN models (see review ).

Many transgenic APP mouse models recapitulate amyloid plaque formation and disease manifestation of
AD and have thereby made essential contributions to understanding Aβ pathology in familial AD. In
comparison, APP rat models often develop less accumulation of Aβ peptide and amyloid plaques. This
cannot be simply explained by lower expression levels of transgenes in rats, or different transgene protein
isoforms, or the applied promoters. One rat model, however, displays full amyloid pathology. Leon et al.
developed an APP transgenic rat model expressing hAPP751 under the control of the murine Thy1.2
[55]
promoter and containing the Swedish and Indiana mutations of APP (McGill-R-Thy1-APP rats) . This rat
model carries one copy of the transgene hemizygously and accordingly presents approximately double the
amount of APP protein (i.e., both endogenous and transgenic) as wild-type rats. Homozygous rats show an
early-onset and progressive accumulation of Aβ peptide starting at 1 week of age and develop extracellular
Aβ deposition at 6 months of age. Particularly, at 20 months of age, McGill-R-Thy1-APP transgenic rats
display dense-core plaques in most brain areas with predominant presence in the entorhinal and parietal
cortices, and hippocampus, the typical brain structures that are vulnerable to AD [56-58] . In summary, despite
the lower expression level of the transgene, McGill-R-Thy1-APP transgenic rats develop early-onset,
progressive, characteristic amyloid plaque pathology making this model valuable for studying Aβ
pathogenesis in a close to physiological condition.

In fact, the distribution and burden of amyloid plaques in AD patients do not correlate with neuronal loss,
disease severity, or disease duration. In contrast, NFT formation strongly correlates with neuronal death
and follows a typical progression from the frontal cortex and the CA1 area of hippocampus to the
anterodorsal thalamus, and in later stages (IV), the CA4 region of hippocampus [59,60] . Instead, NFTs have
[36]
only been found in AD mouse models carrying human mutant tau, mostly with P301L mutation . P301L
missense mutation in tau is the genetic cause of frontotemporal dementia and parkinsonism linked to
chromosome 17 (FTDP-17); this mutation causes tau hyperphosphorylation and its subsequent aggregation
into NFTs [61,62] . Different from FTDP-17, tau is not the only hyperphosphorylated neuronal protein in AD,
and hyperphosphorylated tau is the result of a protein phosphorylation/dephosphorylation unbalance (see