IntroductionIn the past doctors and scientistsbelieved a protein called beta-amyloid was largely responsible for the effectsof neurodegenerative disease yet many patients suffering from neurodegenerativedisease can show very little to no buildup of amyloid plaque in the braintissue (Alzheimer Basics). This forced doctors and scientists to research whatwas really causing the extensive amounts of brain tissue damage. The answer wasa protein found in the brain called Tau.
Tau protein is a significant moleculevital to how the brain rebuilds dendrite structures and repairs damaged axons(Lieff). While the information studied on Tau protein is limited, scientistsknow it is necessary for efficient brain function and physical development.However, tau protein has also recently been linked to numerous patientssuffering from different forms of neurological disease including Alzheimer’sand Chronic Traumatic Encephalopathy (CTE). Scientists refer to these diseasesas Tauopathies because of their high correlation with tau tangle buildup. Overtime, researchers have found that Tau, like all other proteins, can experiencemutations causing it to malfunction.
Tau proteins, more specifically, undergo aprocess called hyperphosphorylation, a mutation that occurs in an alreadysynthesized protein rather than during the DNA replication stage process, and,as a result, the shape of the protein changes altering how it functions. Thisinvestigation aims to explore the correlation between the buildup of tauprotein deposits in the brain and the onset of neurodegenerative disease aswell as explore the frequency of tau buildup due to repetitive head injuriessuch as concussions or traumatic brain injuries (TBIs). By studying how Tauprotein works, and gaining a better understanding of its true purpose in thebrain, scientists will be able to give diagnoses that are more accurate as wellas improve treatment and eventually discover a way to reverse the permanentdamage caused by Tau tangle buildup. Overall Tau protein is an importantmolecule for study and it is necessary to gain more knowledge about how itfunctions, its purpose in the brain, and how to treat tau buildups in order tofurther medical and scientific innovations and research. Brain Structure and Tau Protein FunctionMade up of two distinct parts, thenervous system is responsible for voluntary and involuntary movement as wellsense perception and many other processes in the human body. Those two partsare the peripheral nervous system, which includes the spinal cord and allperipheral nerves, and the central nervous system, which includes the brain andthe brain stem.
The brain is the most complex organ in the human body comprisedof 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 fiberstrands called the corpus collosum which allows neural impulses to makeconnections across the otherwise detached hemispheres. Each hemisphere isdivided into four smaller lobes responsible for different functions such aslanguage 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 ofelectrical impulses across a synapse gap from one nerve cell to another throughthe use of chemicals called neurotransmitters. The body of a nerve cell, calledthe axon, is constructed by small fibers and filaments which, along with afatty layer of insulation called the myelin sheath, help to speed up theprocess of neurotransmission thereby increasing efficiency and reaction time ofbrain processes. These fibers are formed by many smaller monomers joiningtogether. One of these small monomers or subunits is the protein Tau. Withoutthe proteins that make up the neurons, the brain would not be as efficient andcomplex as it is.
However, these same proteins that are so necessary forstructure, support, and function, can also be harmful if their processes aredisrupted or mutated. Tau protein, discovered and named in1975 by Marc Kirschner, is a “factor that promotes the self-assembly oftubulin into microtubules” (Mandelkow). “Microtubules are dynamicstructures that undergo continual assembly and disassembly within the cell.
They function both to determine cell shape… the intracellular transport oforganelles, and the separation of chromosomes during mitosis” (Cooper).
Tau was one of the first proteins to be characterized as a microtubuleassociated protein (MAP) by Kirschner and it sparked new research into Tau’srole as a stabilizer for microtubules inside neurons (Mandelkow). “Theoverall amino acid composition is unusually hydrophilic, consistent with theunfolded character of the protein” (Mandelkow). This special amino acidcomposition allows Tau protein to be highly flexible, mobile, and durable, ableto withstand even heat and acid (Mandelkow). Tau is also able to performtransient interactions with other proteins if need be (Mandelkow). Proteininteractions are highly specific and important to cell function and structure;therefore, Tau’s ability to have this kind of flexibility and durability makesit extremely versatile and efficient.
However, Tau’s large importance in thestructure and function of neurons can have consequences as well. Mutations intau protein can weaken the binding to microtubules; thereby, phosphorylationcan have a structural impact on the protein and nerve cell varying in severitydepending on the number of mutations and strength of the binding sites(Mandelkow). The problem with researching tau protein is that its loose andunfolded structure inhibits imaging technology from locating the protein so itis impossible to know exactly where Tau binds to microtubules and how theydirectly interact (Mandelkow). However, researchers conclude there exists atleast two factors that push tau protein towards aggregation, or the abnormalact of grouping together.
One factor is the microtubule itself. Scientistsbelieve that when tau binds with the microtubules, they act as a sort ofinhibitor, preventing tau from continuing with its unusual behavior(Mandelkow). The other factor is tau protein’s “propensity forbeta-structure” (Mandelkow). This characteristic of the protein isessential to its assembly however when the beta-structures are disrupted, theycan enhance tau’s aggregation process. Overall, tau protein’s unusual behaviorand complex composition make it both essential to brain function and consequential.Simple processes such as hyperphosphorylation or a disruption in thebeta-structure of the protein can cause tau to aggregate abnormally andreplicate unregulated making it a highly reasonable cause of neurodegenerativediseases such as Alzheimer’s disease and Chronic Traumatic Encephalopathy. Alzheimer’s Disease and Tau Protein CorrelationDementia is a generalized term forany 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 ).
Alzheimer’s is a progressive and degenerative disease, meaning itworsens over time, and results in memory loss, difficulty communicating,confusion with time and place, lack of ability to complete basic tasks, andeven behavioral changes as a result of damage to neurons (Alzheimer’s Disease& Dementia). Alzheimer’s is characterized by two types of abnormal lesionsin the brain: beta-amyloid plaques and neurofibrillary tangles. “Beta-amyloidplaques are sticky clumps of protein fragments and cellular material that formoutside and around neurons” (Dementia).
“Neurofibrillary tangles are insolubletwisted fibers composed largely of the protein tau that builds up inside nervecells” (Alzheimer’s Disease & Dementia). While both of these anomalies aresignificant to the development of Alzheimer’s, doctors are not sure whetherthey are causes or by-products of the disease. However, that being said, bothtau tangles and beta-amyloid plaque block neurotransmission and cause neuronsto die off. This leads to atrophy, the shrinking of brain tissue, which worsensthe 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 troubleremembering events, facts, and names (for example) are often the warning signsor first symptoms in individuals with Alzheimer’s disease. Approximately 5.5million individuals currently suffer from Alzheimer’s disease (Alzheimer’sDisease Fact Sheet). 5.3 million of those people are age 65 and older while atleast 200,000 are thought to have Early Onset Alzheimer’s (Alzheimer’s DiseaseFact Sheet). Those most at risk for Alzheimer’s include people age 65 andolder, although younger patients may be diagnosed with Early Onset Alzheimer’sdisease, as well as individuals with Down syndrome. In addition, studiessuggest that African Americans are twice as likely to develop Alzheimer’s asare white people and Hispanics are one and a half times more likely to developAlzheimer’s than white people (Latest Alzheimer’s Facts and Figures).
Furthermore, the disease is more prevalent in females, who account for nearlytwo thirds of the diagnosed population (Latest Alzheimer’s Facts and Figures).The cause of Alzheimer’s is currently unknown although the primary explanationfor Early Onset Alzheimer’s is some type of genetic mutation and Late Onsetstems from a multitude of complications including genetic, lifestyle, andenvironmental factors as well as normal age-related degeneration of braintissues (Alzheimer’s Disease Fact Sheet). Alzheimer’s diagnosed in an individualwith Down syndrome is likely caused by the extra copy of chromosome 21, whichcontains the gene that produces harmful amyloid (Alzheimer’s Disease FactSheet). Although doctors are aware of how Alzheimer’s develops and affects thebrain, the disease can only be definitively diagnosed postmortem due to lack ofresearch and technology. Scientists do not know as much about the disease asthey would like and it has become the forefront of biomedical research; infact, 90% of all information doctors have on Alzheimer’s has been discovered inthe last twenty years alone (Alzheimer’s Disease & Dementia).
Furthermore,it is the third leading cause of death in elderly people, ranked behind heartdisease 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 thedisease takes more lives than breast cancer and prostate cancer combined(Latest Alzheimer’s Facts and Figures). Tau protein plays a large role inAlzheimer’s disease, as it is believed to be directly responsible for theneurofibrillary tangles frequently found in individuals diagnosed with thedisease. In a healthy brain, tau proteins are responsible for the ‘tracks’ thattransport nutrients such as energy and oxygen to the brain tissues (Alzheimer’sBasics). Tau protein helps support the axon, or body of a nerve cell, which isnecessary for neurotransmission. When an individual begins to developAlzheimer’s, these tau proteins collapse and fold in on themselves due to hyperphosphorylation.These folded proteins disrupt the ‘tracks’, disintegrating the transport systemand preventing nutrients from reaching the brain tissues (Alzheimer’s Basics).Without oxygen and energy, the nerve cells begin to die off in a process similarto necrosis called atrophy.
Unlike Beta amyloid, scientists are finding thattau protein is more responsible for the decline in memory and brainfunctioning. Furthermore, whereas beta-amyloid plaques have been found inindividuals showing no signs of Alzheimer’s disease (AD), the neurofibrillarytangles caused by abnormally folded tau proteins more frequently appear inindividuals diagnosed with AD. While there is still debate over whetherneurofibrillary tangles are a cause or by-product of the disease, manyscientists agree it is the relationship and interactions between both tauprotein tangles and beta-amyloid plaque buildups that are to blame for howprogressive and vicious Alzheimer’s disease is (Mandelkow). Extensive researchinto tau protein as a disease-causing agent has shown that while high levels ofhyperphosphorylation is correlated with Alzheimer’s disease, these same levelsare also present in hibernating animals and infants (Mandelkow). That beingsaid, hyperphosphorylation cannot be used as a true indicator ofneurofibrillary tangles and Alzheimer’s disease (Mandelkow). Overall, researchon tau protein has led to the discovery of new processes in the brain and givenrise to several theories about the cause of Alzheimer’s and how doctors mighttreat and cure it. Chronic Traumatic Encephalopathy and Traumatic BrainInjuriesTraumatic Brain injuries are oftenreferred to as concussions and occur when there is a hard blow or sudden joltto 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 traumaticbrain 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, andblurred vision (Traumatic Brain Injury and Concussion). In extreme cases, theindividual may pass out or become unconscious. While the symptoms may varybetween individuals, the overall cause of TBIs remains the same: the brain isnot a fixed structure inside the skull. It is suspended in cerebral-spinalfluid; therefore, when the mechanical movement of the head decelerates oraccelerates at fast paces, there is nothing inside the skull preventing thebrain from continuing with the original motion (Traumatic Brain Injury andConcussion). Newton’s law of inertia can be applied as an explanation to whythis happens. With nothing but cerebral-spinal fluid to slow down the brain inthe event of fast motion, the brain will continue with its original motionuntil another object places a greater force upon it; in this case that force isthe skull (University). The brain hitting against the inner sides of the skullis what causes concussions. In order to function properly, the brain requiresan extremely precise distance and stable balance between neurons (TraumaticBrain Injury and Concussion).
When the brain tissues are jolted, this distanceis disrupted and the neurons become incapable of properly transmitting andreceiving 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, frictioncauses the tissues to stretch and puts strain on axons, which are thin,thread-like neural fibers responsible for the speed and precision oftransmitted neurochemical messages. When an individual suffers from a series ofconcussions or TBIs, the damage accumulates, becomes irreversible, andneurodegenerative diseases such as Chronic Traumatic Encephalopathy (CTE) orAlzheimer’s begin to develop. Concussions and TBIs are quickly becoming a largeproblem frequently seen in hospitals and emergency rooms.
The most commoncauses of TBIs are car accidents although an increasing number of athletessuffer concussions every year. In 2013 alone, there were more than 2.8 millionreported cases of traumatic brain injuries and concussions, including mild TBIsand even those that caused death (Traumatic Brain Injury and Concussion).Furthermore, over the past six years, the number of hospital visits due to TBIshas increased by 50% while hospitalization has increased by 11% and the numberof deaths has increased by 7% (Traumatic Brain Injury and Concussion). In theyear 2012, almost 330,000 children were treated for concussions due torecreation and sports related injuries. “From 2001 to 2012, the rate ofemergency department visits for sports and recreation-related injuries with adiagnosis of concussion or TBI, alone or in combination with other injuries,more than doubled among children (age 19 or younger)” (Traumatic Brain Injuryand Concussion). Within sports there seems to be a trend of which youngerathletes appear more at risk than others.
“Recent research demonstrates thathigh school athletes not only take longer to recover after a concussion whencompared to collegiate or professional athletes, but they also may experiencegreater severity of symptoms and more neurological disturbances as measured byneuropsychological and postural stability tests” (Traumatic Brain Injury andConcussion). Because of the young age of high school athletes, damage to theirbrains tends to be more permanent and consequential especially since it isaffecting the neuroplasticity of the young and developing brain. Furthermore,statistics show that the most at risk male athletes are football players whilethe most at risk female athletes are soccer players and females are two timesmore susceptible than males to get a concussion (Traumatic Brain Injury andConcussion).
Chronic traumatic encephalopathy, or CTE, is classified as aneurodegenerative disease, which occurs over a long period as the brainstructures deteriorate. The disease was first used as a diagnosis in boxershowever in recent decades it has been found in professional football playerswho received numerous concussions and TBIs. Because of this, the disease is gainingwidespread attention and devoted research time from scientists and doctors.Unfortunately, the only way to definitively diagnose an individual with CTE isa postmortem autopsy and there exists no treatment and no cure. The onlypreventative care is to avoid repetitive impacts to the head. The connection between concussionsand tau protein happens after the impact.
The axon of a neuron is extremelyfragile and thin. The microtubules that make up the axon are even more so, heldtogether and protected only by tau protein (Science of CTE). When the skull isimpacted by a large enough force, the axons can be disturbed causing thefragile threads to break thereby stopping the pathway of connections from oneneuron to another. These concussive impacts are extremely dangerous becausethey inhibit neurotransmission however they are relatively easy to diagnose andtreat because the symptoms are generally severe. On the other hand,sub-concussive impacts present a much larger problem because symptoms can be passedoff or ignored and most athletes will convince themselves and their coachesthat they are fine. The consequence of not treating sub-concussive impacts,however, is possible long-term damage. Even if the axon does not rupture, themicrotubules may still break causing the tau protein to unbind from thestructures.
The free tau protein floats around inside the brain tissue andundergoes phosphorylation, meaning the narrow, straight proteins become foldedand clumped (Science of CTE). The mutated tau aggregates with other mutatedproteins floating in the tissue beginning to grow almost like a canceroustumor. Through a process called prion spread, the tau clumps can extend tosurrounding tissues collecting more and more free phosphorylated tau proteincausing further damage even without continuous head injuries or concussiveimpacts (Science of CTE). Moreover, even prion spread can go unnoticed for longperiods of time.
This process of extensive damage is slow and takes time todevelop meaning symptoms can show up years after the damage began. Scientistsare not sure exactly how long it takes after an injury for prion spread tobegin but they do know that CTE works in a very distinctive pattern and as newtechnology and more research undergoes, physicians are working on ways todiagnose and treat CTE (Science of CTE).ConclusionSo, to what extent is tau proteinresponsible for the onset of neurodegenerative disease? While scientists knowtau protein is necessary, they also know it can cause extensive damage if theproteins or neural structures are harmed. Something as simple as hitting theskull against an object can cause damage to brain tissues.
Furthermore, evennormal age-related degeneration of brain tissue can be enhanced as tau proteinacts like a positive feedback loop. The more that tau protein becomes free andaggregated, the more surrounding tissue the tangle affects and the larger itgrows. In conclusion, tau protein is both necessary and malignant. It islargely responsible for the health, structure, and support of the neurons inbrain tissue; however, it can also be somewhat easily disrupted causing theprotein to become harmful and damaging. Two factors appear to play a large rolein the stabilization of tau protein: the attachment to microtubules themselvesand the protein’s propensity for beta-structure (Mandelkow). Both of thesefactors play a large role in how the tau protein interacts with other moleculesin the neuron and inhibiting mutation and aggregation.
With regards toAlzheimer’s disease (AD) and how tau protein plays a role in causation, it isspeculated that these mutations and disruptions in tau are partly responsiblefor the extensive and irreversible damage present in individuals who sufferfrom AD. Tau proteins’ unusually hydrophilic and straight composition changesinto a hydrophobic and curled protein that folds in on itself and aggregateswith similarly mutated tau proteins, creating large neurofibrillary tangles inthe brain tissue that disrupt neurotransmission and cause atrophy (Mandelkow).The damage tends to begin in the hypothalamus which explains why memory loss isthe most common and defining characteristic of Alzheimer’s disease.
When itcomes to traumatic brain injuries, repetitive concussions, and chronictraumatic encephalopathy (CTE), friction from the brain tissues rubbing againstthe skull after periods of quick acceleration or deceleration, or in otherwords concussive and sub-concussive impacts, causes neural tissue to becomestretched and irritated (Traumatic Brain Injury and Concussion). Concussive andsub-concussive impacts can have two consequences: either the axon rupturescompletely and neural pathways break or the axon stays intact while themicrotubules take the damage (Science of CTE). Damaged microtubules release tauprotein from binding sites and the free tau protein becomes clumped, turninginto neurofibrillary tangles over time. These tangles can cause atrophy in aprocess called prion spread (Science of CTE). Overall, it is important to notethat while scientists are not yet entirely sure about what causes tau protein’sunusual behavior, improved technology and further research are makingexamination of the protein easier and more in depth.
The more doctors learnabout tau, the faster they find a way to locate, diagnose, and treatneurofibrillary tangles and neurodegenerative disease.