Introduction amyloid plaque in the brain tissue (Alzheimer

Introduction

In the past doctors and scientists
believed a protein called beta-amyloid was largely responsible for the effects
of neurodegenerative disease yet many patients suffering from neurodegenerative
disease can show very little to no buildup of amyloid plaque in the brain
tissue (Alzheimer Basics). This forced doctors and scientists to research what
was really causing the extensive amounts of brain tissue damage. The answer was
a protein found in the brain called Tau. Tau protein is a significant molecule
vital to how the brain rebuilds dendrite structures and repairs damaged axons
(Lieff). While the information studied on Tau protein is limited, scientists
know it is necessary for efficient brain function and physical development.
However, tau protein has also recently been linked to numerous patients
suffering from different forms of neurological disease including Alzheimer’s
and Chronic Traumatic Encephalopathy (CTE). Scientists refer to these diseases
as Tauopathies because of their high correlation with tau tangle buildup. Over
time, researchers have found that Tau, like all other proteins, can experience
mutations causing it to malfunction. Tau proteins, more specifically, undergo a
process called hyperphosphorylation, a mutation that occurs in an already
synthesized protein rather than during the DNA replication stage process, and,
as a result, the shape of the protein changes altering how it functions. This
investigation aims to explore the correlation between the buildup of tau
protein deposits in the brain and the onset of neurodegenerative disease as
well as explore the frequency of tau buildup due to repetitive head injuries
such as concussions or traumatic brain injuries (TBIs). By studying how Tau
protein works, and gaining a better understanding of its true purpose in the
brain, scientists will be able to give diagnoses that are more accurate as well
as improve treatment and eventually discover a way to reverse the permanent
damage caused by Tau tangle buildup. Overall Tau protein is an important
molecule for study and it is necessary to gain more knowledge about how it
functions, its purpose in the brain, and how to treat tau buildups in order to
further medical and scientific innovations and research.

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Brain Structure and Tau Protein Function

Made up of two distinct parts, the
nervous system is responsible for voluntary and involuntary movement as well
sense perception and many other processes in the human body. Those two parts
are the peripheral nervous system, which includes the spinal cord and all
peripheral nerves, and the central nervous system, which includes the brain and
the brain stem. The brain is the most complex organ in the human body comprised
of several parts and billions of nerve cells. The cerebrum, or cerebral cortex,
has two parts, the left and right hemispheres, connected by a bundle of fiber
strands called the corpus collosum which allows neural impulses to make
connections across the otherwise detached hemispheres. Each hemisphere is
divided into four smaller lobes responsible for different functions such as
language comprehension, motor function, cognitive ability, hearing, and seeing.
The brain tissue itself consists of billions of nerve cells called neurons.
Neurons are responsible for neurotransmission, which is the passing of
electrical impulses across a synapse gap from one nerve cell to another through
the use of chemicals called neurotransmitters. The body of a nerve cell, called
the axon, is constructed by small fibers and filaments which, along with a
fatty layer of insulation called the myelin sheath, help to speed up the
process of neurotransmission thereby increasing efficiency and reaction time of
brain processes. These fibers are formed by many smaller monomers joining
together. One of these small monomers or subunits is the protein Tau. Without
the proteins that make up the neurons, the brain would not be as efficient and
complex as it is. However, these same proteins that are so necessary for
structure, support, and function, can also be harmful if their processes are
disrupted or mutated.

Tau protein, discovered and named in
1975 by Marc Kirschner, is a “factor that promotes the self-assembly of
tubulin into microtubules” (Mandelkow). “Microtubules are dynamic
structures that undergo continual assembly and disassembly within the cell.
They function both to determine cell shape… the intracellular transport of
organelles, and the separation of chromosomes during mitosis” (Cooper).
Tau was one of the first proteins to be characterized as a microtubule
associated protein (MAP) by Kirschner and it sparked new research into Tau’s
role as a stabilizer for microtubules inside neurons (Mandelkow). “The
overall amino acid composition is unusually hydrophilic, consistent with the
unfolded character of the protein” (Mandelkow). This special amino acid
composition allows Tau protein to be highly flexible, mobile, and durable, able
to withstand even heat and acid (Mandelkow). Tau is also able to perform
transient interactions with other proteins if need be (Mandelkow). Protein
interactions are highly specific and important to cell function and structure;
therefore, Tau’s ability to have this kind of flexibility and durability makes
it extremely versatile and efficient. However, Tau’s large importance in the
structure and function of neurons can have consequences as well. Mutations in
tau protein can weaken the binding to microtubules; thereby, phosphorylation
can have a structural impact on the protein and nerve cell varying in severity
depending on the number of mutations and strength of the binding sites
(Mandelkow). The problem with researching tau protein is that its loose and
unfolded structure inhibits imaging technology from locating the protein so it
is impossible to know exactly where Tau binds to microtubules and how they
directly interact (Mandelkow). However, researchers conclude there exists at
least two factors that push tau protein towards aggregation, or the abnormal
act of grouping together. One factor is the microtubule itself. Scientists
believe that when tau binds with the microtubules, they act as a sort of
inhibitor, preventing tau from continuing with its unusual behavior
(Mandelkow). The other factor is tau protein’s “propensity for
beta-structure” (Mandelkow). This characteristic of the protein is
essential to its assembly however when the beta-structures are disrupted, they
can enhance tau’s aggregation process. Overall, tau protein’s unusual behavior
and complex composition make it both essential to brain function and consequential.
Simple processes such as hyperphosphorylation or a disruption in the
beta-structure of the protein can cause tau to aggregate abnormally and
replicate unregulated making it a highly reasonable cause of neurodegenerative
diseases such as Alzheimer’s disease and Chronic Traumatic Encephalopathy.

Alzheimer’s Disease and Tau Protein Correlation

Dementia is a generalized term for
any decline in mental ability severe enough to interfere with daily life
(Dementia). Alzheimer’s disease is the most common form of dementia,
accounting for 60-80% of all dementia cases (Alzheimer’s Disease &
Dementia). Alzheimer’s is a progressive and degenerative disease, meaning it
worsens over time, and results in memory loss, difficulty communicating,
confusion with time and place, lack of ability to complete basic tasks, and
even behavioral changes as a result of damage to neurons (Alzheimer’s Disease
& Dementia). Alzheimer’s is characterized by two types of abnormal lesions
in the brain: beta-amyloid plaques and neurofibrillary tangles. “Beta-amyloid
plaques are sticky clumps of protein fragments and cellular material that form
outside and around neurons” (Dementia). “Neurofibrillary tangles are insoluble
twisted fibers composed largely of the protein tau that builds up inside nerve
cells” (Alzheimer’s Disease & Dementia). While both of these anomalies are
significant to the development of Alzheimer’s, doctors are not sure whether
they are causes or by-products of the disease. However, that being said, both
tau tangles and beta-amyloid plaque block neurotransmission and cause neurons
to die off. This leads to atrophy, the shrinking of brain tissue, which worsens
the Alzheimer’s symptoms and continues the cycle of deterioration of the brain
(Alzheimer’s Disease Fact Sheet). The damage tends to begin in the hippocampus,
an area of the brain responsible for memory, which explains why trouble
remembering events, facts, and names (for example) are often the warning signs
or first symptoms in individuals with Alzheimer’s disease. Approximately 5.5
million individuals currently suffer from Alzheimer’s disease (Alzheimer’s
Disease Fact Sheet). 5.3 million of those people are age 65 and older while at
least 200,000 are thought to have Early Onset Alzheimer’s (Alzheimer’s Disease
Fact Sheet). Those most at risk for Alzheimer’s include people age 65 and
older, although younger patients may be diagnosed with Early Onset Alzheimer’s
disease, as well as individuals with Down syndrome. In addition, studies
suggest that African Americans are twice as likely to develop Alzheimer’s as
are white people and Hispanics are one and a half times more likely to develop
Alzheimer’s than white people (Latest Alzheimer’s Facts and Figures).
Furthermore, the disease is more prevalent in females, who account for nearly
two thirds of the diagnosed population (Latest Alzheimer’s Facts and Figures).
The cause of Alzheimer’s is currently unknown although the primary explanation
for Early Onset Alzheimer’s is some type of genetic mutation and Late Onset
stems from a multitude of complications including genetic, lifestyle, and
environmental factors as well as normal age-related degeneration of brain
tissues (Alzheimer’s Disease Fact Sheet). Alzheimer’s diagnosed in an individual
with Down syndrome is likely caused by the extra copy of chromosome 21, which
contains the gene that produces harmful amyloid (Alzheimer’s Disease Fact
Sheet). Although doctors are aware of how Alzheimer’s develops and affects the
brain, the disease can only be definitively diagnosed postmortem due to lack of
research and technology. Scientists do not know as much about the disease as
they would like and it has become the forefront of biomedical research; in
fact, 90% of all information doctors have on Alzheimer’s has been discovered in
the last twenty years alone (Alzheimer’s Disease & Dementia). Furthermore,
it is the third leading cause of death in elderly people, ranked behind heart
disease and cancer, and the sixth overall leading cause of death in Americans.
Since the year 2000, deaths due to Alzheimer’s have increased by 89% and the
disease takes more lives than breast cancer and prostate cancer combined
(Latest Alzheimer’s Facts and Figures).

Tau protein plays a large role in
Alzheimer’s disease, as it is believed to be directly responsible for the
neurofibrillary tangles frequently found in individuals diagnosed with the
disease. In a healthy brain, tau proteins are responsible for the ‘tracks’ that
transport nutrients such as energy and oxygen to the brain tissues (Alzheimer’s
Basics). Tau protein helps support the axon, or body of a nerve cell, which is
necessary for neurotransmission. When an individual begins to develop
Alzheimer’s, these tau proteins collapse and fold in on themselves due to hyperphosphorylation.
These folded proteins disrupt the ‘tracks’, disintegrating the transport system
and preventing nutrients from reaching the brain tissues (Alzheimer’s Basics).
Without oxygen and energy, the nerve cells begin to die off in a process similar
to necrosis called atrophy. Unlike Beta amyloid, scientists are finding that
tau protein is more responsible for the decline in memory and brain
functioning. Furthermore, whereas beta-amyloid plaques have been found in
individuals showing no signs of Alzheimer’s disease (AD), the neurofibrillary
tangles caused by abnormally folded tau proteins more frequently appear in
individuals diagnosed with AD. While there is still debate over whether
neurofibrillary tangles are a cause or by-product of the disease, many
scientists agree it is the relationship and interactions between both tau
protein tangles and beta-amyloid plaque buildups that are to blame for how
progressive and vicious Alzheimer’s disease is (Mandelkow). Extensive research
into tau protein as a disease-causing agent has shown that while high levels of
hyperphosphorylation is correlated with Alzheimer’s disease, these same levels
are also present in hibernating animals and infants (Mandelkow). That being
said, hyperphosphorylation cannot be used as a true indicator of
neurofibrillary tangles and Alzheimer’s disease (Mandelkow). Overall, research
on tau protein has led to the discovery of new processes in the brain and given
rise to several theories about the cause of Alzheimer’s and how doctors might
treat and cure it.

Chronic Traumatic Encephalopathy and Traumatic Brain
Injuries

Traumatic Brain injuries are often
referred to as concussions and occur when there is a hard blow or sudden jolt
to the head that results in the disruption of normal brain functioning;
however, similar to how individuals react differently to diseases or medication,
every concussion is unique in its symptoms and how it affects the individual
(Traumatic Brain Injury and Concussion). The most common symptoms of traumatic
brain injuries, or TBIs, include frequent headaches, difficulty concentrating,
changes in sleep patterns, loss of memory, problems with speech or balance,
nausea, personality changes, increased sensitivity to light and sound, and
blurred vision (Traumatic Brain Injury and Concussion). In extreme cases, the
individual may pass out or become unconscious. While the symptoms may vary
between individuals, the overall cause of TBIs remains the same: the brain is
not a fixed structure inside the skull. It is suspended in cerebral-spinal
fluid; therefore, when the mechanical movement of the head decelerates or
accelerates at fast paces, there is nothing inside the skull preventing the
brain from continuing with the original motion (Traumatic Brain Injury and
Concussion). Newton’s law of inertia can be applied as an explanation to why
this happens. With nothing but cerebral-spinal fluid to slow down the brain in
the event of fast motion, the brain will continue with its original motion
until another object places a greater force upon it; in this case that force is
the skull (University). The brain hitting against the inner sides of the skull
is what causes concussions. In order to function properly, the brain requires
an extremely precise distance and stable balance between neurons (Traumatic
Brain Injury and Concussion). When the brain tissues are jolted, this distance
is disrupted and the neurons become incapable of properly transmitting and
receiving messages. When the balance between neurons is disrupted, the neurons’
efficiency at processing information decreases, hence the resulting symptoms.
Furthermore, as the brain tissues move along the inside of the skull, friction
causes the tissues to stretch and puts strain on axons, which are thin,
thread-like neural fibers responsible for the speed and precision of
transmitted neurochemical messages. When an individual suffers from a series of
concussions or TBIs, the damage accumulates, becomes irreversible, and
neurodegenerative diseases such as Chronic Traumatic Encephalopathy (CTE) or
Alzheimer’s begin to develop. Concussions and TBIs are quickly becoming a large
problem frequently seen in hospitals and emergency rooms. The most common
causes of TBIs are car accidents although an increasing number of athletes
suffer concussions every year. In 2013 alone, there were more than 2.8 million
reported cases of traumatic brain injuries and concussions, including mild TBIs
and even those that caused death (Traumatic Brain Injury and Concussion).
Furthermore, over the past six years, the number of hospital visits due to TBIs
has increased by 50% while hospitalization has increased by 11% and the number
of deaths has increased by 7% (Traumatic Brain Injury and Concussion). In the
year 2012, almost 330,000 children were treated for concussions due to
recreation and sports related injuries. “From 2001 to 2012, the rate of
emergency department visits for sports and recreation-related injuries with a
diagnosis of concussion or TBI, alone or in combination with other injuries,
more than doubled among children (age 19 or younger)” (Traumatic Brain Injury
and Concussion). Within sports there seems to be a trend of which younger
athletes appear more at risk than others. “Recent research demonstrates that
high school athletes not only take longer to recover after a concussion when
compared to collegiate or professional athletes, but they also may experience
greater severity of symptoms and more neurological disturbances as measured by
neuropsychological and postural stability tests” (Traumatic Brain Injury and
Concussion). Because of the young age of high school athletes, damage to their
brains tends to be more permanent and consequential especially since it is
affecting the neuroplasticity of the young and developing brain. Furthermore,
statistics show that the most at risk male athletes are football players while
the most at risk female athletes are soccer players and females are two times
more susceptible than males to get a concussion (Traumatic Brain Injury and
Concussion). Chronic traumatic encephalopathy, or CTE, is classified as a
neurodegenerative disease, which occurs over a long period as the brain
structures deteriorate. The disease was first used as a diagnosis in boxers
however in recent decades it has been found in professional football players
who received numerous concussions and TBIs. Because of this, the disease is gaining
widespread attention and devoted research time from scientists and doctors.
Unfortunately, the only way to definitively diagnose an individual with CTE is
a postmortem autopsy and there exists no treatment and no cure. The only
preventative care is to avoid repetitive impacts to the head. 

The connection between concussions
and tau protein happens after the impact. The axon of a neuron is extremely
fragile and thin. The microtubules that make up the axon are even more so, held
together and protected only by tau protein (Science of CTE). When the skull is
impacted by a large enough force, the axons can be disturbed causing the
fragile threads to break thereby stopping the pathway of connections from one
neuron to another. These concussive impacts are extremely dangerous because
they inhibit neurotransmission however they are relatively easy to diagnose and
treat because the symptoms are generally severe. On the other hand,
sub-concussive impacts present a much larger problem because symptoms can be passed
off or ignored and most athletes will convince themselves and their coaches
that they are fine. The consequence of not treating sub-concussive impacts,
however, is possible long-term damage. Even if the axon does not rupture, the
microtubules may still break causing the tau protein to unbind from the
structures. The free tau protein floats around inside the brain tissue and
undergoes phosphorylation, meaning the narrow, straight proteins become folded
and clumped (Science of CTE). The mutated tau aggregates with other mutated
proteins floating in the tissue beginning to grow almost like a cancerous
tumor. Through a process called prion spread, the tau clumps can extend to
surrounding tissues collecting more and more free phosphorylated tau protein
causing further damage even without continuous head injuries or concussive
impacts (Science of CTE). Moreover, even prion spread can go unnoticed for long
periods of time. This process of extensive damage is slow and takes time to
develop meaning symptoms can show up years after the damage began. Scientists
are not sure exactly how long it takes after an injury for prion spread to
begin but they do know that CTE works in a very distinctive pattern and as new
technology and more research undergoes, physicians are working on ways to
diagnose and treat CTE (Science of CTE).

Conclusion

So, to what extent is tau protein
responsible for the onset of neurodegenerative disease? While scientists know
tau protein is necessary, they also know it can cause extensive damage if the
proteins or neural structures are harmed. Something as simple as hitting the
skull against an object can cause damage to brain tissues. Furthermore, even
normal age-related degeneration of brain tissue can be enhanced as tau protein
acts like a positive feedback loop. The more that tau protein becomes free and
aggregated, the more surrounding tissue the tangle affects and the larger it
grows. In conclusion, tau protein is both necessary and malignant. It is
largely responsible for the health, structure, and support of the neurons in
brain tissue; however, it can also be somewhat easily disrupted causing the
protein to become harmful and damaging. Two factors appear to play a large role
in the stabilization of tau protein: the attachment to microtubules themselves
and the protein’s propensity for beta-structure (Mandelkow). Both of these
factors play a large role in how the tau protein interacts with other molecules
in the neuron and inhibiting mutation and aggregation. With regards to
Alzheimer’s disease (AD) and how tau protein plays a role in causation, it is
speculated that these mutations and disruptions in tau are partly responsible
for the extensive and irreversible damage present in individuals who suffer
from AD. Tau proteins’ unusually hydrophilic and straight composition changes
into a hydrophobic and curled protein that folds in on itself and aggregates
with similarly mutated tau proteins, creating large neurofibrillary tangles in
the brain tissue that disrupt neurotransmission and cause atrophy (Mandelkow).
The damage tends to begin in the hypothalamus which explains why memory loss is
the most common and defining characteristic of Alzheimer’s disease. When it
comes to traumatic brain injuries, repetitive concussions, and chronic
traumatic encephalopathy (CTE), friction from the brain tissues rubbing against
the skull after periods of quick acceleration or deceleration, or in other
words concussive and sub-concussive impacts, causes neural tissue to become
stretched and irritated (Traumatic Brain Injury and Concussion). Concussive and
sub-concussive impacts can have two consequences: either the axon ruptures
completely and neural pathways break or the axon stays intact while the
microtubules take the damage (Science of CTE). Damaged microtubules release tau
protein from binding sites and the free tau protein becomes clumped, turning
into neurofibrillary tangles over time. These tangles can cause atrophy in a
process called prion spread (Science of CTE). Overall, it is important to note
that while scientists are not yet entirely sure about what causes tau protein’s
unusual behavior, improved technology and further research are making
examination of the protein easier and more in depth. The more doctors learn
about tau, the faster they find a way to locate, diagnose, and treat
neurofibrillary tangles and neurodegenerative disease.