eBook: Advancing Neuroscience Research - 12

inhibits the aggregation of human tau and only express
4R tau isoforms, unlike the mixture of 3R and
4R isoforms in AD. To overcome the non-formation
of NFTs, transgenic mice were modified to express
4R human tau with a P301L or P301S mutation.
However, this reduces the accuracy of the mouse
model, as these mutations are not associated with
AD and may potentially influence toxicity or interaction
with the amyloid plaques through pathways
not reflective of AD. Furthermore, the overexpression
of these mutated tau proteins results in motor
deficits not associated with AD and interferes with
cognitive testing.3
Figure 1. Amyloid aggregation associated with
neurodegenerative diseases. Reproduced from Stroo et al.2
that aggregates may differ between neurodegenerative
diseases, the disease progression and clinical
indications are similar. To study these diseases,
most of these experimental models are animal
models involving the use of transgenic rodent animals
expressing human genes to induce pathogenic
protein aggregation, especially AD. Similarly,
chemically or physically induced animal models
are also employed as these models are able to capture
certain symptoms of diseases that may not be
modeled in transgenic mice, such as PD.
AD disease models use transgenic mice: these models
generally only exhibit amyloid accumulation, a
defining characteristic of AD, but lack neurofibrillary
tangle (NFT) development. NFTs are a secondary
characteristic of AD that are insoluble twisted
fibers inside of brain cells. These tangles are formed
through a misfolded tau protein that are the constituents
of microtubules. These microtubules
transport nutrients and other molecules between
nerve cells; the formation of NFTs causes the collapse
of these microtubule structures. Within the
transgenic mouse models, endogenous mouse tau
To model PD, toxin-induced mouse models such as
6-OHDA and MPTP, are the classical model choice
and are widely in use. By introducing neurotoxins
into the animal models, rapid degeneration of dopaminergic
neurons in PD-related regions leads
to a robust and well-characterized motor deficit.
However, this model only simulates the clinical
symptoms and lacks the molecular pathology of
PD, such as alpha-synuclein (α-syn) accumulation
and Lewy bodies. On the other hand, transgenic
mice with mutations in SNCA, LRRK2, Parkin, PINK1,
and DJ-1 are also used to study PD. These genetic
mutations are linked to inherited forms of PD and
express the implicated proteins. However, these
transgenic mouse models often lack the same robust
nigrostriatal degeneration (loss of dopamine
neurons) and do not have the same consistent,
reproducible motor deficits as with the toxin-induced
models.
Pre-formed fibrils and formation
Unlike transgenic and toxin-induced mouse models,
PFFs provide a different and more cost-effective
perspective into neurodegenerative disease
research. Whereas transgenic mouse models focus
on selecting certain genetic mutations to express
pathogenic proteins endogenously, the genetic
differences between host and target could cause
12
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