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1 DFF 38 Ce 14 C 86 Fef 05 F 4
1 DFF 38 Ce 14 C 86 Fef 05 F 4
MINI-REVIEWS
Upola Zaman
Undergraduate Division, University California Berkeley
CONTACT Upola Zaman, upola_zaman@berkeley.edu Undergraduate, Department of Molecular Cell biology, University of California Berkeley
© 2023 Taylor & Francis
NEUROGENESIS 2
the molecular mechanisms involved in AD and developed into humans. As of 2021, this low
predict disease before onset.2 Based on the predictive validity is evidenced by the 200
pathology of AD and the nature of scientific clinical drugs that failed during clinical trials.2
research, scientists should consider the Unlike the mice and rat models used, marine
following four aspects: resulting face, based animal models can fulfill the four
construct validity, predictive validity, and criteria.
research logistics.2 Resulting face involves
how well the model can replicate human AD
Small-Scale Marine Models
symptoms.2 Construct validity is defined as
how well the model demonstrates the Primary research on the use of the marine
biological cause of AD.2 Predictive Validity is snail Aplysia Californica as a model in AD
how well the model can translate success in research concluded that Aplysia is an example
AD therapeutics clinically for humans.2 of a suitable new model.5 In particular,
Research logistics involve the cost, ease of Aplysia’s well mapped nervous system and
maintenance, and breeding constraints faced multivalence in nature help to truly capture
by labs.2 the resulting face of AD.5 Due to Aplysia
Current models tend to fail the established containing orthologs of AB and tau, artificially
criteria. Current vertebrate models are unable inducing mutant human tau in Aplysia can
to truly reconstruct the complexity of AD in create AD tauopathies or tau neurofibrillary
humans, failing the criteria of resulting face.5 tangles.2 Creating the primary hallmarks of AD
Many mouse models do not perform well in fulfills Aplysia’s constructing validity criteria.
terms of construct validity. In the PDAPP There has also been success in translating
mouse line, the hallmarks of AD never memory research from Aplysia to humans.2 As
develop during study.2 In the murine APP for research logistics, invertebrate models like
mouse models, AD and FTD mutations were Aplysia Californica allow for better genetic
required to replicate AD pathology due to manipulation especially for expressing APP,
being unable to form plaque naturally from AB, and tau found in humans.6 This animal
three amino acid substitutions in amyloid model appears promising for AD research and
beta sequence.2 However, in humans FAD only predicting therapeutic success.
requires one mutation, not multiple.2 The Zebrafish is another example of a smaller
murine APP Knock In models tried to correct scale model that can be used to study AD.
this with targeted gene editing that allowed Zebrafish are an emerging model for studying
mAPP cleaving at the “human equivalent neurogenesis.7 Zebrafish have more
position.”2 However, the use of multiple APP persistence of radial glial cells to act like stem
mutations to more closely model human cells, have a higher volume of neuroblasts,
pathology was still needed.2 Putting and can also regenerate the brain, making
mutations in to recreate accumulation can them ideal for studying physiopathological
create issues in construct validity.2. Current diseases like AD.7 Authors like Mhalhel et al.,
models also can not translate treatments agree with zebrafish becoming an ideal
NEUROGENESIS 4
model, noting that they have become more in can be seen in a medical case of naturally
use over the past 20 years in studying various occurring epilepsy in sea lions. Dominic acid
biomedical fields including neurodegenerative poisoning caused sea lions to have
disorders.8 In terms of the resulting face, hippocampal damage and progressively
zebrafish can be induced to form AB plaques.8 worsening brain circuitry.9 The key behind
This model can also express human tau solving sea lion health was by using research
proteins within 2 days of experimentation done in solving temporal lobe epilepsy in
when under control of the GATA2 promoter humans.9 Through research conducted by
and hyperphosphorylation of tau protein.8 neurosurgeons at UCSF, a cell therapy of
Zebrafish are also great models for introducing transplant embryonic MGE was
constructing validity. Zebrafish have a 70% developed and successfully transcribed into
homology to the human genome, sharing sea lions.9 The success in predictive validity of
important orthologous AD genes to humans marine medicine in epilepsy demonstrates the
including psen1 and psen2.8 More capacity large marine animals have in AD.
importantly, zebrafish share homologous Specific large animal models that can be
APPa and APPb genes with humans.8 used in AD research include odontocetes,
Zebrafish can be considered a model of high otherwise known as toothed whales. Primary
interest due to their ability to help study FAD. research analyzing several regions of the brain
FAD is typically associated with APP genes, from dead odontocetes reveals the extent
psen1, and psen2.8 In terms of research large marine animals successfully fulfill the
logistics, zebrafish have ease of maintenance, resulting face criteria.10 Generally, AD
growth, and suitability for optical monitoring.8 progression in humans involves AD-associated
This marine based animal model is a unique APs being found in the frontal, temporal, and
approach of using marine organisms in the AD occipital lobes.10. When progressing, it then
treatment pipeline, specifically in the form of spreads throughout the cerebrocortical
research. areas.10 For references, the human frontal
lobe's equivalent is the orbital lobe of
Large Scale Marine Models dolphins while the parietal lobe is equivalent
to the cerebral cortex of dolphins.10. Within
Moving on from smaller scale marine models, the regions analyzed, lesions made from the
larger marine models may be more beneficial accumulation of APs and pTau were
for studying AD. It should be acknowledged distributed in the brain in regions analogous
that larger animals can negatively impact to those in humans.10 The presence of both
research logistics due to their high costs, APs and pTaus simultaneously point to a
breeding, and conflicts with pharmaceutical spontaneous AD-like pathology.10 The ability
testing.2 However, larger animals are to share the same spontaneous development
associated with better predictive validity and of AD demonstrates odontocetes' capacity to
could help reduce expenses caused by failures be an excellent model in research.
in clinical testing.2 The association between
larger marine animals and predictive validity
NEUROGENESIS 5
Though many of the current drugs in AD two-hundred AD drugs that went to clinical
only target one area, a multi-directional trials ended up failing.2 In contrast, two select
approach may prove to be more successful.15 marine based drugs were able to make it past
AD has many hallmarks and causes a myriad phase I clinical trials. One marine based
of effects to the human body. Examples of Alzheimer’s drug undergoing Phase I of
some of the AD targets include Ab, tau, clinical trials as of 2021 is known as
GluN3A, acetylcholinesterase, and inhibition Bryostatin.16 A second phase I drug, GTS-21
of parts of the mitochondria.15 Marine drugs' made from a marine alkaloid anabaseine, was
structural composition and mechanism of once known for Alzheimer’s, but is more
actions allow it to consistently target multiple beneficial for obesity.16 Not many marine
AD targets such as the five mentioned.3 The drugs for AD currently exist, but those that do
unique qualities of marine drugs allow it to tend to have higher success passing clinical
not only eliminate the drug synthesis process, trials. According to Hu et al., the only limiting
but also stand itself apart from terrestrial and factor for marine drug success is the lack of
synthetic products.3 current clinical trials stemming from “lack of
Of the multi-directional approaches, collaboration between disciplines.”
multi-target-directed ligands (MTDLs) are
highly praised.15 MTDLs are designed by Excavation
creating hybrid molecules with a
cholinesterase inhibitor and other biological Once research is completed, the process of
molecules that can target different parts of developing therapeutics begins. One of the
AD.3 An example of designing MTDLs would main components of developing therapeutics
be combining marine alkaloids for the is the excavation of compounds necessary to
cholinesterase and another marine create drugs. One avenue of ways marine
compound. MTDLs treat AD by inhibiting a science is used in biomedicine is creating
protein kinase (PKCθ or PKCδ), reducing AB biomolecules/products since it is of high
levels, and targeting serine or glycogen interest to pharmaceuticals and has a high
kinase.15 interest in economic activities.1 However,
marine drugs have many drawbacks. Outside
of the almost 1.8 billion goes towards
Current AD Clinical Trials developing new molecular treatments,
After research, treatments for AD are created. excavating from marine ecosystems can be an
Many AD drugs that have made it to clinical additional price added on.17 Although marine
trials were quickly rejected due to causing compounds contain important high value
health defects that were not present in molecules, organisms have a low amount of
animal models.2 In 2013, four out of the 13 it.11 This would make excavating logistically
drugs that inhibit cholinesterase, a target for difficult and potentially harmful to the
AD therapeutics, were taken out of the biodiversity of marine life.11 There are
market due to causing liver toxicity.12 By 2021, solutions in place to overcome this.
NEUROGENESIS 7