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Advanced Neurology Alzheimer’s and Parkinson’s disease rodent models

of age. Furthermore, in the J20 mice, significant neuronal model, Aβ aggregates manifest as the first pathological
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loss is found in the CA1 area of the hippocampus, feature, with neuronal immunoreactivity observed around
starting at 6 months of age. In addition to these classic 4 months of age in neocortical regions and at 6 months in the
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overexpression lines, mice with genetic modification based CA1 area of the hippocampus. Senile plaque accumulation
on the Tet-off mechanism have also been identified. In this becomes apparent in 12-month-old animals, indicating
model, the gene promoter of APP (Swe and Ind) transgene progressive protein deposition. Tau NFTs emerge in mice
is responsive to tetracycline. The presence of Aβ starts of the same age, corroborating the Aβ cascade hypothesis
from 2 months of age, and by 9 months of age, amyloid and closely mimicking the disease progression observed
plaques are already observable in mice. A significant and in the patients. However, this model’s protracted timeline
progressive neuronal deficit is also evident, especially presents a research disadvantage, requiring long-term
in the dentate gyrus region of the hippocampus. The colony maintenance. In terms of behavioral deficits, studies
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Tet-off-APP mice offer the advantage of transgene have shown memory and spatial learning impairments in
expression control, where Aβ expression can be activated 3×Tg mice as early as 6.5 months of age, observed across
or deactivated by the presence or absence of tetracycline both sexes. 94
or its analog, such as doxycycline. This feature allows
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for the activation of Aβ expression in adulthood, thereby 4.1.5. APP NL-G-F and APP NL-F
eliminating Aβ developmental phenotypes unrelated to The APP NL-G-F KI mice, also known as APP NL-G-F/NL-G-F
AD. Furthermore, another AD model identified involves and App NL-G-F , harbor three distinct APP mutations: the
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mice carrying the APP E693Δ-Tg (Osaka) mutation, APP K670_M671delinsNL (Swedish) “NL,” the APP I716F
originally reported in early-onset Japanese patients. The (Iberian) “F,” and the APP E693G (Arctic) “G.” Conversely,
mutation within exon 17 results in the loss of a glutamate the APP NL-F KI mice, or APP NL-F/NL-F , possess only two
residue at position 693 of the APP and 22 of the Aβ of these mutations: the Swedish “NL” and the Iberian
peptide. This mutation induces amyloid accumulation in “F.” Unlike other APP models, both APP NL-G-F and
cortical and hippocampal neurons without the presence APP NL-F models do not exhibit APP overexpression;
of extracellular Aβ plaques, representing a model for Aβ instead, they maintain endogenous levels of APP, with
oligomers. Despite the absence of plaques, these animals the inserted mutations leading to enhanced total Aβ
still develop tau tangles, neuronal loss, and memory production (“NL”), altered Aβ42/Aβ40 ratio (“F”), and
deficits. 91 increased Aβ aggregation (“G”). The APP NL-F/NL-F model
demonstrates a less pronounced pathological phenotype,
4.1.4. 3×Tg with the development of Aβ plaques reported at 6 months
The 3×Tg or 3×Tg-AD mice are considered triple- of age. In contrast, Aβ plaque deposition in APP NL-G-F/NL-G-F
transgenic due to their possession of three mutated mice begins at 2 months of age, peaking at 7 months.
genes: APPswe, PS1M146V, and tauP301L. These genetic Concurrent with Aβ plaque formation, both models
alterations drive the progressive and age-dependent exhibit microglia and astrocyte activation. Synaptic loss has
development of Aβ plaques and NFTs in mice, especially in also been reported in 7 – 12-month-old APP NL-F/NL-F mice
the hippocampus and cerebral cortex regions. The 3×Tg and in 3 to 4-month-old APP NL-G-F/NL-G-F mice. Cognitive
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model is generated is derived from single-cell embryos impairment manifests in 6-month-old APP NL-G-F/NL-G-F
of the homozygous knock-in (KI) mouse PS1M146V, mice and 18-month-old APP NL-F/NL-F mice. However, NFTs
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in which two independent transgenes encoding human and neurodegeneration have not been observed in these
APPswe and human tauP301L are co-microinjected. mice. 95-97
A notable advantage of this model lies in its uniform
genetic background, reducing genetic variability typical of 4.1.6. APOE
crosses between different lineages. The co-microinjected The APOE KO (apolipoprotein E knockout) mice
genes integrated into the same locus, minimizing the feature an inactivation of the endogenous mouse APOE
likelihood of independent separation. Moreover, the by homologous recombination and the insertion of a
PS1M146V mutation is inherent in the embryonic cells of neomycin cassette. These mice exhibit elevated total plasma
the KI mouse, facilitating the maintenance of 3×Tg animals cholesterol levels and remain unaffected by age or gender.
as if they were a single transgenic line, even with three Notably, fatty streaks in the proximal aorta are observable
distinct mutated genes. This feature streamlines colony by 3 months of age, with lesion severity escalating with age
maintenance, enhancing efficiency and cost-effectiveness. and progressing to lesions characterized by diminished
Furthermore, these animals exhibit both Aβ plaques and lipid but elongated cells. These APOE KO mice are useful
NFTs, the main histopathological markers of AD. In this for studying the role of APOE in AD. Around 17 months

Volume 3 Issue 3 (2024) 10 doi: 10.36922/an.2903