Modern Approaches to Human Diseases – Question 1 – Alejandro Garcia u1817199
Poor animal models have slowed the discovery of effective cures for neurodegenerative
diseases such as Alzheimer’s and Parkinson’s Disease. Discuss
Introduction
Having a model system with a high contrast validity and predictive validity is vital for the
development of new treatments and the ability to study the mechanism of neuropathology.
Alzheimer’s and Parkinson’s Disease are two of the most prominent neurodegenerative
diseases in the Western World. Alzheimer’s Disease (AD) is characterised by neuronal loss in
the sulci and gyri leading to clinical manifestations like impairment of cognition and
memory. The neuropathological hallmarks of Parkinson’s Disease (PD) are the loss of
dopaminergic neurons in the substania nigra pars compacta (SNc) and the formation of
proteinaceous inclusions called Lewy Bodies (LBs). This leads to an involuntary “rolling-pin”
motion, rigidity and a shuffling gait movement. There is a need to develop novel therapeutic
strategies to alleviate the burden on society of these diseases, the use of animal models is
the first step in this process. In this essay I will examine the different animal models that are
currently being used for the discovery of effective cures and assess whether they have
slowed down this process.
Neurotoxin model for Parkinson’s Disease
Figure 1. Parkinson’s affected neuron will release less
dopamine compared to a normal neuron.
Source: anti-agingfirewalls.com
In PD the death of the dopaminergic neurons in the SNc, will lead to the clinical
manifestations described. As we are killing dopaminergic neurons, the amount of
extracellular dopamine will reduce, therefore the aim of any therapeutic strategy is to
replenish dopamine in the brain (Figure 1).
A rodent model using neurotoxin involves the use of 6-hydroxydopamine (6-OHDA), a
neurotoxic synthetic compound that will selectively target nigrostriatal dopaminergic
neurons in rats (Ungerstedt, 1968), thereby eliciting the same effect as in patients. After
accumulating in the cytosol, 6-OHDA will promote the formation of reactive oxygen species
(ROS) and quinines by auto-oxidation (Simola, Morelli and Carta, 2007), which also occurs in
the Parkinsonian brain. The compound will destroy the dopaminergic neurons in the SNc in
less than 24hrs (Jeon et al, 1995), therefore providing a stable and reliable model for new
treatments as it reproduces many of the effects in patients.
One of the issues with this model is how the neurotoxin molecule is administered. Due to it
being hydrophilic, it is unable to cross the Blood-Brain-Barrier (BBB) and therefore the
animal requires a direct injection. This invasive approach could lead to complications like a
brain inflammatory response which may alter the results. A more suitable way to introduce
this compound would by placing it in a microbubble and cause the opening of the BBB by
Modern Approaches to Human Diseases – Question 1 – Alejandro Garcia u1817199
using a focused ultrasound (Figure 2) (Sheikov et al, 2004, Pardridge, 2020). This approach
could improve the administration of the compound into the model, and therefore offer an
alternative means of discovery of new therapeutic methods.
Figure 2. Schematic
representation of using a
focused ultrasound drug
delivery system to
temporarily open the
blood-brain barrier
Credit: Tao Sun/Bringham and
Women;s Hospital; adapted by
KurzweilAI
Another reason why neurotoxin models are poor to study PD in, is that the production of
Lewy body-like inclusions are not seen but it does interact with a-synuclein (Lindgren et al,
2012). This suggests that eventhough the model does work in destroying dopamine neurons
leading to the manifestations seen, if it doesn’t produce Lewy bodies, the model is not
replicating the scenario in a Parkinsonian brain, so the results differ from reality.
However, this model has been able to reproduce several key processes like the generation
of ROS resulting in oxidative stress inducing cell death (Singh et al, 2010). Therefore, some
may argue that it has not slowed down the development of novel treatments.
Pharmacological Models - Reserpine for Parkinson’s Disease
Another rodent model you can use is one with reserpine. Reserpine is a drug that will
deplete storage of dopamine by inhibiting VMAT (Guldberg, 1971). The effect of L-DOPA
being able to reverse the effects of reserpine pre-treatment in humans (Degkwitz et al,
1960) led to a potential way to discover the symptomatic efficacy of new drugs for PD. This
demonstrates how a model actually sped up the discovery of effective cures and not slow
them down.
Mouse Models for Alzheimer’s Disease
There are multiple mouse models that are used for AD. In order to produce a mouse model,
you take the mutation of interest and put the whole gene into the mouse (transgenic
mouse). For studying the effects of AD, the most used mutation is the APP695 (Amyloid
precursor protein) which is overexpressed in mice, to observe whether it produces plaques,
and cause the pathogenesis seen in AD patients.
One of the mouse models used is the triple transgenic mouse (3xTg-AD). They have a knockin presenilin gene from a human, inserted into their genome. This mutation will affect the
way presenilin processes the APP, as the way it is processed depends heavily on the
possibility of an individual developing AD. By knowing where the deposition of amyloid
plaques starts, we could be able to design a suitable pharmaceutical intervention to prevent
the accumulation of these plaques. This mouse model was used by Oddo et al (2003) to
show that these plaques are not initiating in the hippocampus but in the neocortex, which is
different to humans. They did however, see that the phosphorylation of tau starts in the
hippocampus and progresses to the neocortex – which is similar to humans. The reason why
this is a poor model is because, eventhough plaques and tangles were formed there was no
Modern Approaches to Human Diseases – Question 1 – Alejandro Garcia u1817199
degeneration of neurons, which is the best correlate to the symptoms demonstrated by AD
patients. This has made the ability to produce a drug from this model very hard, as we have
not been able to reproduce the disease in animal models.
Transgenic rat model for Alzheimer’s Disease
The lack of treatments developed on mouse models, led to the use of a wider variety of
model species. In 2018, Petrasek et al, established the so-called “McGill Transgenic Rat
Model” which was a success, as it was able to do what the mouse model couldn’t. There was
accumulation of plaques, neuroinflammation, and the steady deterioration of cognitive
functions. However, the models’ motor and social alterations require more scientific work to
see if they are homologous with patients of AD. The data obtained from this, could dictate
whether the model could be used in future studies. The innovation of this animal model has
allowed the ability to find an effective cure, therefore the statement that animal models
have slowed the process of discovery is controversial.
Conclusion
Eventhough the therapies which have been assayed on neurodegenerative animal models
have not worked in patients with an established pathology, the therapies developed could
be used in preventing disease progression towards dementia (Cuadrado-Tejedor and GarciaOsta, 2014). In some cases, these poor animal models even if they have not been able to aid
in the discovery of effective cures for AD and PD, have been successful in preventing disease
progression in other neurodegenerative diseases, so it is unreasonable to say these poor
animal models have had no effect on the development of therapies. There is a new hope in
using transgenic mice to try to find a cure for neurodegenerative diseases as we have a
model which elicits homogenous effects in vivo to patients.
Modern Approaches to Human Diseases – Question 1 – Alejandro Garcia u1817199
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Modern Approaches to Human Diseases – Question 1 – Alejandro Garcia u1817199
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