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2023, VOL. N/A, NO. N/A,(8 pages)

https //doi hyperlinktodoc

MINI-REVIEWS

The Extent of Marine Biomedicine Influence on Functional Diseases

like Alzheimers

Upola Zaman
Undergraduate Division, University California Berkeley

Introduction pipeline. However, marine biomedicine hasn’t

had a large traction due to research not being
Alzheimer’s Disease (AD) is the most common
geared to those with medical backgrounds.3
neurodegenerative disease, with 5 million
Therefore this review intends to cover the
cases reported annually.1 AD is becoming
extent of development in marine biomedicine
more widespread worldwide as the biggest
on functional diseases like Alzheimers with
risk factor for AD continues to increase: Age.
the framework of medical development. A
By 2050, the number of cases of AD is
review needs to be done since the extent of
expected to triple.2 The significance of this
this research only began to take off 3 years
issue requires a more thoughtful look into the
ago in 2020.1 As of right now, there are only
AD drug pipeline: Research, Drug Design,
smaller sub reviews of everything scattered
Excavation, and Clinical Testing. Currently
around instead of one comprehensive review
there is an underutilized potential of AD that
detailing the development of biomedicine.
has the ability to advance understanding of
Having it all in one area can help show
the field. This potential can be unlocked
medical researchers what they can do later
through the use of marine biomedicine, which
and what area needs to be focused on to
has the ability to influence all aspects of the
develop marine biomedicine further.

CONTACT Upola Zaman, upola_zaman@berkeley.edu Undergraduate, Department of Molecular Cell biology, University of California Berkeley
© 2023 Taylor & Francis
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broken down by discussing marine based

Marine Biomedicine and AD Drug Pipeline research tools, treatments alongside past
clinical trials, and finally excavation methods
Cheng discusses in a 1982 editorial the early
for marine compounds.
developments of marine organism research in
biomedicine. Prominent examples in the
article include Elie Metchnikoff’s experiment Research Tools
of rose thorns into echinoderm larvae, the
This first step in the pipeline involves using
first use of a squid's giant nerve axon to study
animal models. Animal models are a primary
nerve cells in a more advanced fashion, and
tool in the research process. Discussion of this
the role of marine echinoderms (starfish) in
section first consists of establishing the
researching microtubules.4 The applications of
criteria of what makes a good animal model.
marine science to neuroscience research can
When establishing the criteria, examples used
be extended to AD. AD, due to being
in current research as well as their pitfalls are
neurodegenerative, can be prevented through
expanded on to give a better idea of what a
neuroprotection. Neuroprotection is the
new model would need. Once criteria
mechanism that attempts to counter
selection is understood, a discussion of
neurodegeneration through chemical,
smaller scale marine models and larger scale
biological, or psychological means.1 In the
models follow. The stages of research in
recent years following 2020, there has been a
Alzheimer's can range from the cellular level
shift in focus to finding natural substances for
to the macroscopic level depending on what
improving neuroprotection, including those
the researcher is trying to accomplish. Marine
that are marine based.1 Incorporating marine
models have the capability to tend to both
science to AD medicine would help medical
situations based on its scale.
researchers create neuroprotection for their
patients.
Due to the medical field and AD research Criteria
mainly centering on an application driven
Considering suitable animal models boils
approach, this review will discuss the extent
down to how well they can replicate AD
of marine biomedicine on AD. When first
pathology. Typically, AD involves AB plaques,
approaching a topic like AD, medical
tangle formation, and neurodegeneration.2
professionals will want to conduct research.
These are hallmark symptoms in Alzheimer’s
After conducting research, they will then turn
disease progression.2 True replication of AD
to creating treatments. The treatment process
models would involve the development of AD
requires first creating the drug or treatment
hallmark symptoms over decades of time.2 As
design and then gathering compounds after
long as it is within the model's bounds, many
deciding the success rate of a possible
cases of AD can be studied. An animal model
treatment. The last step involves clinical trials.
of high interest is one that can study Familial
This four step process encapsulates the AD
early onset group (FAD).2 FAD helps to study
drug pipeline. Due to this, the review will be

the molecular mechanisms involved in AD and
predict disease before onset.2 Based on the
pathology of AD and the nature of scientific
research, scientists should consider the
following four aspects: resulting face,
construct validity, predictive validity, and
research logistics.2 Resulting face involves
how well the model can replicate human AD
symptoms.2 Construct validity is defined as
how well the model demonstrates the
biological cause of AD.2 Predictive Validity is
how well the model can translate success in
AD therapeutics clinically for humans.2
Research logistics involve the cost, ease of
maintenance, and breeding constraints faced
by labs.2
Current models tend to fail the established
criteria. Current vertebrate models are unable
to truly reconstruct the complexity of AD in
humans, failing the criteria of resulting face.5
Many mouse models do not perform well in
terms of construct validity. In the PDAPP
mouse line, the hallmarks of AD never
develop during study.2 In the murine APP
mouse models, AD and FTD mutations were
required to replicate AD pathology due to
being unable to form plaque naturally from
three amino acid substitutions in amyloid
beta sequence.2 However, in humans FAD only
requires one mutation, not multiple.2 The
murine APP Knock In models tried to correct
this with targeted gene editing that allowed
mAPP cleaving at the “human equivalent
position.”2 However, the use of multiple APP
mutations to more closely model human
pathology was still needed.2 Putting
mutations in to recreate accumulation can
create issues in construct validity.2. Current
models also can not translate treatments
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developed into humans. As of 2021, this low
predictive validity is evidenced by the 200
clinical drugs that failed during clinical trials.2
Unlike the mice and rat models used, marine
based animal models can fulfill the four
criteria.
Small-Scale Marine Models
Primary research on the use of the marine
snail Aplysia Californica as a model in AD
research concluded that Aplysia is an example
of a suitable new model.5 In particular,
Aplysia’s well mapped nervous system and
multivalence in nature help to truly capture
the resulting face of AD.5 Due to Aplysia
containing orthologs of AB and tau, artificially
inducing mutant human tau in Aplysia can
create AD tauopathies or tau neurofibrillary
tangles.2 Creating the primary hallmarks of AD
fulfills Aplysia’s constructing validity criteria.
There has also been success in translating
memory research from Aplysia to humans.2 As
for research logistics, invertebrate models like
Aplysia Californica allow for better genetic
manipulation especially for expressing APP,
AB, and tau found in humans.6 This animal
model appears promising for AD research and
predicting therapeutic success.
Zebrafish is another example of a smaller
scale model that can be used to study AD.
Zebrafish are an emerging model for studying
neurogenesis.7 Zebrafish have more
persistence of radial glial cells to act like stem
cells, have a higher volume of neuroblasts,
and can also regenerate the brain, making
them ideal for studying physiopathological
diseases like AD.7 Authors like Mhalhel et al.,
agree with zebrafish becoming an ideal

model, noting that they have become more in
use over the past 20 years in studying various
biomedical fields including neurodegenerative
disorders.8 In terms of the resulting face,
zebrafish can be induced to form AB plaques.8
This model can also express human tau
proteins within 2 days of experimentation
when under control of the GATA2 promoter
and hyperphosphorylation of tau protein.8
Zebrafish are also great models for
constructing validity. Zebrafish have a 70%
homology to the human genome, sharing
important orthologous AD genes to humans
including psen1 and psen2.8 More
importantly, zebrafish share homologous
APPa and APPb genes with humans.8
Zebrafish can be considered a model of high
interest due to their ability to help study FAD.
FAD is typically associated with APP genes,
psen1, and psen2.8 In terms of research
logistics, zebrafish have ease of maintenance,
growth, and suitability for optical monitoring.8
This marine based animal model is a unique
approach of using marine organisms in the AD
treatment pipeline, specifically in the form of
research.
Large Scale Marine Models
Moving on from smaller scale marine models,
larger marine models may be more beneficial
for studying AD. It should be acknowledged
that larger animals can negatively impact
research logistics due to their high costs,
breeding, and conflicts with pharmaceutical
testing.2 However, larger animals are
associated with better predictive validity and
could help reduce expenses caused by failures
in clinical testing.2 The association between
larger marine animals and predictive validity
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can be seen in a medical case of naturally
occurring epilepsy in sea lions. Dominic acid
poisoning caused sea lions to have
hippocampal damage and progressively
worsening brain circuitry.9 The key behind
solving sea lion health was by using research
done in solving temporal lobe epilepsy in
humans.9 Through research conducted by
neurosurgeons at UCSF, a cell therapy of
introducing transplant embryonic MGE was
developed and successfully transcribed into
sea lions.9 The success in predictive validity of
marine medicine in epilepsy demonstrates the
capacity large marine animals have in AD.
Specific large animal models that can be
used in AD research include odontocetes,
otherwise known as toothed whales. Primary
research analyzing several regions of the brain
from dead odontocetes reveals the extent
large marine animals successfully fulfill the
resulting face criteria.10 Generally, AD
progression in humans involves AD-associated
APs being found in the frontal, temporal, and
occipital lobes.10. When progressing, it then
spreads throughout the cerebrocortical
areas.10 For references, the human frontal
lobe's equivalent is the orbital lobe of
dolphins while the parietal lobe is equivalent
to the cerebral cortex of dolphins.10. Within
the regions analyzed, lesions made from the
accumulation of APs and pTau were
distributed in the brain in regions analogous
to those in humans.10 The presence of both
APs and pTaus simultaneously point to a
spontaneous AD-like pathology.10 The ability
to share the same spontaneous development
of AD demonstrates odontocetes' capacity to
be an excellent model in research.

Treatments
The chemical makeup of marine life is ten
times more biodiverse than terrestrial and
recently more scientists have begun
implementing marine science elements into
biomedicine.1 These elements can include
marine compounds such as bacterioplankton,
marine microalgae, marine macroalgae,
sponges, tunicates, and arthropods.11 This
section will first go over exogenously taking
marine compounds as it would be the less
arduous method to get approved for patient
use. Directional approaches in making marine
based therapeutics will then be covered to
give a better understanding of how to design
marine based drugs. Finally, the current state
of Alzheimer’s clinical trials, as well as the
status of any marine based drugs is
highlighted to give context to the
underutilized potential of AD research.
Exogenous Drug Alternative Treatments
One way to treat AD is based on increasing
neuroprotection with Docosahexaenoic acid
(DH).12 Low levels of Docosahexaenoic acid
(DH), is normally associated as a sign for AD.
Obtaining DH through marine organisms
exogenously (fish oil, krill oil. And algae) can
help increase neuroprotection against AD by
inhibiting accumulation of B-amyloid.12
Specific food sources of DH include Atlantic
salmon.12 The concept of exogenously taking
marine biomolecules is supported by a
primary research article discussing how the
Kinh people of Beibu Gulf exogenously
derived biocompounds to boost health in
areas like neurogenesis.13 This study was
conducted by analyzing donated specimens,
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photos of specimens, and asking locals the
common names for marine organisms.13
Further research on the Kinh people and how
they used such marine organisms was also
provided.13 The study concluded that the Kinh
would frequently use animal meat, shells, and
objects as a primary material in medicine13..
Directional Approaches for Therapeutics
Many studies aim to discuss recent
compounds restructured from 2018 to 2020
that aid in neuroprotection. Within the
reviews, many biocompounds that helped in
single-directional approaches to AD were
listed. One such compound includes
polysaccharides such as Alginate.1 These
compounds are in high abundance and have
unique chemical properties that help in AD
treatment. Compounds derived from marine
polysaccharides tend to be superior to those
derived from terrestrial compounds.1 Alginate
in particular can prevent neurodegeneration
by inhibiting amyloid-B and increasing
mitochondrial membrane potential.1
Alkaloids are another marine compound
that can target various areas in the brain
including ABeta production, NFT formation,
AChe and pro inflammatory factor inhibition,
and stabilizing nChARS.14 These alkaloids are
typically derived from the marine sponge
Ianthella.14 Alkaloids, due to their
multifaceted nature, can be used in both
single directional and multidirectional
approaches. For single directional, alkaloids
can either target cholinesterase enzymes,
inhibit A Beta aggregation, or inhibit protein
kinases.15

Though many of the current drugs in AD
only target one area, a multi-directional
approach may prove to be more successful.15
AD has many hallmarks and causes a myriad
of effects to the human body. Examples of
some of the AD targets include Ab, tau,
GluN3A, acetylcholinesterase, and inhibition
of parts of the mitochondria.15 Marine drugs'
structural composition and mechanism of
actions allow it to consistently target multiple
AD targets such as the five mentioned.3 The
unique qualities of marine drugs allow it to
not only eliminate the drug synthesis process,
but also stand itself apart from terrestrial and
synthetic products.3
Of the multi-directional approaches,
multi-target-directed ligands (MTDLs) are
highly praised.15 MTDLs are designed by
creating hybrid molecules with a
cholinesterase inhibitor and other biological
molecules that can target different parts of
AD.3 An example of designing MTDLs would
be combining marine alkaloids for the
cholinesterase and another marine
compound. MTDLs treat AD by inhibiting a
protein kinase (PKCθ or PKCδ), reducing AB
levels, and targeting serine or glycogen
kinase.15
Current AD Clinical Trials
After research, treatments for AD are created.
Many AD drugs that have made it to clinical
trials were quickly rejected due to causing
health defects that were not present in
animal models.2 In 2013, four out of the 13
drugs that inhibit cholinesterase, a target for
AD therapeutics, were taken out of the
market due to causing liver toxicity.12 By 2021,
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two-hundred AD drugs that went to clinical
trials ended up failing.2 In contrast, two select
marine based drugs were able to make it past
phase I clinical trials. One marine based
Alzheimer’s drug undergoing Phase I of
clinical trials as of 2021 is known as
Bryostatin.16 A second phase I drug, GTS-21
made from a marine alkaloid anabaseine, was
once known for Alzheimer’s, but is more
beneficial for obesity.16 Not many marine
drugs for AD currently exist, but those that do
tend to have higher success passing clinical
trials. According to Hu et al., the only limiting
factor for marine drug success is the lack of
current clinical trials stemming from “lack of
collaboration between disciplines.”
Excavation
Once research is completed, the process of
developing therapeutics begins. One of the
main components of developing therapeutics
is the excavation of compounds necessary to
create drugs. One avenue of ways marine
science is used in biomedicine is creating
biomolecules/products since it is of high
interest to pharmaceuticals and has a high
interest in economic activities.1 However,
marine drugs have many drawbacks. Outside
of the almost 1.8 billion goes towards
developing new molecular treatments,
excavating from marine ecosystems can be an
additional price added on.17 Although marine
compounds contain important high value
molecules, organisms have a low amount of
it.11 This would make excavating logistically
difficult and potentially harmful to the
biodiversity of marine life.11 There are
solutions in place to overcome this.

Research on computer aided solutions are
one avenue to better excavate biocompounds.
Primary research on a computer aided drug
discovery design (CADD) was shown to
decrease the expensive cost for developing
new molecular treatments.17 CADD works by
giving guidance and synthesis of possible
marine therapeutics without the use of a
sample.17 Having a CADD to decide whether
collecting a sample would result in a
successful drug would be beneficial to reduce
such costs, especially since a sample of the
material is not needed to perform analysis.17
Biotechnology such as CADD is necessary for
progress in AD treatments.
Despite the drawbacks in marine drug
excavation, there are concrete steps in
biotechnology taken to quickly overturn
them. The use of biotechnology currently in
the status quo, outside of CADD, also includes
the creation of a custom targeting system to
more easily conduct cell based therapy in sea
lions.9 Many authors advocate for the
development of marine biotechnology such as
aquaculture, genetic engineering, fermenter
cultivation, chemical synthesis, and more to
solve this extraction issue.11 Through
innovation to aid in excavation and treatment,
marine prospection increases.17 More
organizations can also conduct marine drug
discovery due to decreased cost, guidance in
the drug discovery process, and protection of
marine biodiversity.17
Concluding Remarks
Marine Biomedicine has had a large impact
on AD research within recent years. Many of
these developments would not have been
NEUROGENESIS 7
possible without investment into
biotechnology. Authors such as Marisa Silva
highly advocate for more development of
marine biotechnology for extraction,
isolation, characterization, and efficiency of
the drug discovery process. Innovations such
as the CADD for the AD drug discovery
process and a custom targeting system
software for implementation of treatment
have also helped to decrease costs and time
for the AD research pipeline.17, 9 Continuing
with developing these tools can help to truly
advance the field of AD research. Future
research also needs to be able to cut down on
clinical trial costs and perform more
successful trials for AD derived marine drugs.
More awareness on the efficacy of marine
based drugs and models can help draw
traction from medical professionals to
conduct clinical trials. Increasing medical
professional comfort and knowledge in
marine biomedicine in AD research can also
help increase progress in the AD treatment
forefront.
Disclosure of potential conflicts of interest
No potential conflicts of interest were
disclosed.
Funding
No funding has been used.
ORCID (N/A)

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