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Page 6 of 29 Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19

[69]
model expressing mutant APP and PSIN1(PS1 M146L ) mediated by adeno-associated viruses .

Very recently, Pang and colleagues generated an APP KI rat model, App NL-G-F rats, which carry three family
[70]
App mutations G676R, F681Y, and R684H . Both homo- and heterozygous rats manifested amyloid
plaques rapidly at 1 and 4 months of age, respectively. Notably, the amyloid plaque manifestation in
App NL-G-F rats preceded faster in females compared to males . Whether this sex difference in Aβ aggregation
[71]
can be linked to the higher incidence rates of AD in women than in men requires further investigation.
Interestingly, aggregated tau was found in 12-month-old homozygous App NL-G-F rats and further manifested
into NFTs at 22 months of age. Increased gliosis, apoptotic cell death and brain atrophy have been observed
in App NL-G-F rats at 12 months of age and older.

Taken together, several APP rat models have shown common AD neuropathological features in AD-affected
brain areas, in particular NFT formation, a key pathogenic event in the disease process, which have not been
recapitulated in APP mouse models. The lack of the 4R isoforms in mice may be the cause for the two
rodents’ differing abilities to model human tau pathology.

Neuropathological phenotypes in genetic rat models of Parkinson’s disease: PINK1 KO, DJ-1 KO, and a-
synuclein BAC rats
The characteristic neuropathological features of PD are intracellular α-synuclein positive inclusions known
as Lewy bodies (LBs), and selective neuronal loss in the substantia nigra, which is strongly related to
mitochondrial dysfunction (see review ). About 20 genes have been identified to cause familial PD,
[72]
inherited in an autosomal dominant or recessive mode. In the following, we will focus on three PD genetic
rat models, which made significant contributions to the PD field as compensations for mouse models: the
α-synuclein transgenic rats, PINK1 KO rats, and DJ-1-KO rats.

α-synuclein BAC transgenic rat model
The major component of LBs is α-synuclein, which is encoded by the SNCA gene. This was the first gene
revealed to have a causal link to PD development. To this date, six autosomal dominant SNCA point
mutations (A53T, A30P, E46K, G51D, H50Q, and A53E) have been identified . Moreover, duplication,
[73]
triplication and quadruplication of the SNCA locus have been reported to be causal in genetically unrelated
PD families [74-77] . A number of transgenic mice models bearing human mutant or wild-type SNCA have been
generated. Many of these models exhibit proteinase K resistant, detergent-insoluble, and thioflavin S
[78]
positive α-synuclein aggregates (see review ). Mouse models also show a neuronal loss in PD-relevant
brain areas, that is, substantia nigra, neocortex, and hippocampus [79-83] . An α-synuclein BAC transgenic rat
model using a bacterial artificial chromosome (BAC) construct consisting of full-length human wild-type
SNCA locus with the upstream regulatory promoter sequences has been generated by the Riess lab . These
[84]
BAC transgenic rats showed key pathological features of PD, including progressive misfolding and
accumulation of α-synuclein aggregates, striatal dopamine depletion, decreased TH-positive cell numbers,
and characteristic dark dopamine neurons in the substantia nigra. These pathological features have been
modeled comparably in α-synuclein transgenic mice. However, with larger body sizes, rats offer unique
possibilities for surgical manipulations of the brain, serial sampling of cerebrospinal fluid and blood, and
brain imaging.

Rat models for autosomal recessive mutations
Autosomal recessive forms of PD commonly present an early onset phenotype [85,86] . All three known
autosomal recessive PD genes, PARKIN, PINK1, and DJ-1, are closely associated with mitochondrial
dysfunction [87-89] . The PTEN-induced kinase 1 (PINK1) and Parkin are involved in the same pathway leading