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

PD, they are also found in other conditions, such as Lewy the GTPase domain. 15,75 Mice overexpressing G2019S or
body disease and multiple system atrophy, which share R1441C/G mutations are commonly used as PD models.
this protein aggregation, although each has its specificities. These mice exhibit varying degrees of dopaminergic system
A decrease in TH and dopamine levels was observed in deficits, including impaired dopamine transmission, motor
these mice. In addition, many studies have not reported dysfunction, and dopaminergic neuronal degeneration,
significant dopaminergic neurodegeneration in transgenic although generally without significant synucleinopathy. 76-78
α-Syn mice, as reviewed previously. Meanwhile, other
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studies leveraging cell-specific overexpression of α-Syn 4. Most used AD models
have demonstrated dopaminergic neuronal loss. 61 The search yielded 3,835 studies (Figure 3). After removing
duplicates and restricting the year range, 3,809 articles were
3.2.2. Parkin/PINK1
screened for eligibility. Studies involving human subjects
The PARK2 gene, also known as PRKN, encodes the protein (n = 21), non-rodent models (n = 75), models unrelated to
Parkin. PARK2 mutations have been reported in many cases AD (n = 428), non-original articles (n = 268), those lacking
of juvenile parkinsonism. Parkin functions as a ubiquitin clarity on the studied subjects/models (n = 26), and those
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E3 ligase and plays an important role in mitochondrial unavailable (n = 30) were excluded. Of the 2,961 studies
quality control. Mutations in the PARK2 gene impair protein included, 2,432 (82.1%) studies used genetic models,
degradation, leading to the accumulation of proteins and 478 (16.1%) used induced models, 37 (1.2%) used a
toxic substrates, as well as mitochondrial dysfunction. 63,64 combined model involving two different AD models in the
PTEN-induced putative kinase 1, also called PINK1, is a same animal, and 14 (0.5%) used both models (Figure 4A).
mitochondrial protein kinase (located at the PARK6 locus) The trend over the past 5 years is depicted in Figure 4B.
that regulates Parkin activity through phosphorylation. Figures 4C and D illustrate that a total of 3,058 AD models
Both proteins participate in the autophagy induction of were used in the past 5 years, with 2,527 (82.6%) being
impaired mitochondria. 65,66 Mutations in PINK1 have genetic models, 494 (16.2%) being induced models, and
also been associated with autosomal recessive PD. Parkin 37 (1.2%) being a combined model.
knockout mice, along with PINK1 knockout animals, Figures 4E and F provide detailed information
are considered classic genetic PD models. These mice about the AD models used in the past 5 years. The four
show mitochondrial dysfunction and oxidative stress. most used rodent AD models in the past 5 years were
However, there is no consensus on whether these models APP/PS1 (24.8%), 5×FAD (20.5%), APP-based models
exhibit α-Syn aggregation and dopaminergic neuronal (which encompass all models in which APP was altered
loss. 67-70 Some studies have reported similar numbers of to generate an AD model) (10.9%), and 3×Tg (10.5%).
dopaminergic neurons in triple knockout mice for Parkin, Aβ-induced models, in which Aβ oligomers are usually
Pink1, and DJ-1 at different ages (3, 16, and 24 months injected into the mice’s brain, were used in 7.8% of the
old) compared to wild-type animals. Neuronal death was studies. Genetic modifications of tau were used in 6.8%
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reported in older Parkin knockout mice at 120 weeks of age of the studies. The APP NL-F/APP NL-G-F mice and
(over 2 years old), representing that these models require injections of streptozotocin (STZ) were each used in 3.4%
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substantial time and resources to maintain. Therefore, of the studies. In addition, 2.4% of the selected studies used
while these models may be useful for studying the genetic injections of scopolamine as an AD model. The senescence-
aspects of PD related to these specific mutations, they may accelerated mouse prone line 8 (SAMP8) mice (classified
not be suitable for research focusing on neuroprotection. here as a genetic model despite their natural occurrence,
as detailed below), injections of D-galactose (D-gal) and/
3.2.3. LRRK2
or AlCl , APOE transgenic mice, LPS injections, and the
3
Leucine-rich repeat kinase-2 (LRRK2), also referred to as transgenic mice PS2APP were each used in <2% of the
dardarin, is a large protein containing kinase and GTPase studies. Furthermore, 1.2% of the studies used combined
domains. LRRK2 is widely distributed throughout the models, such as the investigation in which the animal
brain, with particularly high expression in the nigrostriatal was subjected to more than one model (e.g., J20 [hAPP]
system. The LRRK2 protein plays multiple roles in cellular mice crossed with P301L [Tau] mice, and their offspring
processes, including autophagy, mitochondrial functions, were used in the study; or APP [Tg2576] transgenic mice
endocytosis, and vesicular trafficking. Mutations in the receiving intracerebroventricular Aβ injections). Another
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LRRK2 gene have been reported in families with autosomal- 1.6% of the studies used other models, such as the Tau-R3-
dominant, late-onset parkinsonism. The most common induced, acrolein-induced, and p25-inducible transgenic
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mutations in LRRK2 are G2019S and R1441C/G, primarily mouse. In addition, 0.8% of the studies reported new AD
affecting the enzymatic domain of the protein, mainly models for the first time.

Volume 3 Issue 3 (2024) 7 doi: 10.36922/an.2903