Neurofibrillary tangle
Encyclopedia
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
tau protein that are most commonly known as a primary marker of Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. Their presence is also found in numerous other diseases known as Tauopathies. Little is known about their exact relationship to the different pathologies.
Formation
Neurofibrillary tangles are formed by hyperphosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of a microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
-associated protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
known as tau, causing it to aggregate, or group, in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or "paired helical filaments"). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in disease or play a more peripheral role.
Cytoskeletal changes
Three different maturation states of NFT have been defined using anti-tau and anti-ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
immunostaining
Immunostaining
Immunostaining is a general term in biochemistry that applies to any use of an antibody-based method to detect a specific protein in a sample. The term immunostaining was originally used to refer to the immunohistochemical staining of tissue sections, as first described by Albert Coons in 1941...
. At stage 0 there are morphologically normal pyramidal cell
Pyramidal cell
Pyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
s showing diffuse or fine granular cytoplasmic staining with anti-tau. In other words cells are healthy with minimal tau presence; at stage 1 some delicate elongate inclusions
Inclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
are stained by tau antibodies (these are early tangles); stage 2 is represented by the classic NFT demonstration with anti-tau staining ; stage 3 is exemplified by ghost tangles (tangles outside of cells where the host neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
has died), which are characterized by a reduced anti-tau but marked anti-ubiquitin immunostaining.
Causes
Mutated Tau
The traditional understanding is that tau binds to microtubules and assists with their formation and stabilization. However when tau is hyperphosphorylated, it is unable to bind and the microtubules become unstable and begin disintegrating. The unbound tau clumps together in formations called neurofibrillary tangles. More explicitly, intracellular lesions known as pretangles develop when tau is phosphorylated excessively and on improper amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. These lesions, over time, develop into filamentous
Protein filament
In biology, a filament is a "long chain of proteins, such as those found in hair, muscle, or in flagella". They are often bundled together for strength and rigidity. Some cellular examples include:*Actin filaments*Microtubules*Intermediate filaments...
neurofibrilary tangles (NFTs) which interfere with numerous intracellular functions. Seeking a reliable animal model for tau-related pathologies, researchers expressed the human mutant P301L tau gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in adult mice. This experiment resulted in the formation of neurofibrillary tangles and pretangle formations. The human mutant P301 tau gene is associated with frontotemporal dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
with parkinsonism, another tauopathy associated with NFTs. It was found that the degree of tau pathology was dependent on time and the level of gene expression. Groups receiving a combination of a promoter and enhancer
Enhancer
Enhancer may mean one of the following:* Enhancer , a short region of DNA that can increase transcription of genes* Exciter , audio effect unit.* Enhancer is a French Rapcore band....
in the vector
Vector (molecular biology)
In molecular biology, a vector is a DNA molecule used as a vehicle to transfer foreign genetic material into another cell. The four major types of vectors are plasmids, viruses, cosmids, and artificial chromosomes...
saw increased tau expression, as early as 3 weeks after vector injection, which was measured using a Western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...
. These groups also showed a greater pathology compared to those with less expression of the mutant tau. Additionally, NFTs were clearly detected by immunoelectron microscopy at 4 months but not at 2 months. However, at both 2 and 4 months, pretangle-like structures were observed suggesting the NFT formation is not complete by 4 months and will continue to progress with time.
Traumatic Brain Injury
Preliminary research indicates that iron deposits due to hemorrhaging, following traumatic brain injuryTraumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
(TBI), may increase tau pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
. While TBI does not routinely lead to accelerated NFT formation, further work may determine if other blood components or factors unrelated to hemorrhages are involved in this TBI-induced augmentation of tau pathology. NFTs are most commonly seen associated with repetitive mild TBI as opposed to one instance of severe traumatic brain injury. For example the clinical syndrome of dementia pugilistica
Dementia pugilistica
Dementia pugilistica is a type of neurodegenerative disease or dementia, which may affect amateur or professional boxers as well as athletes in other sports who suffer concussions...
, otherwise known as punch-drunk syndrome found in boxers, is highly associated with NFTs and neuropil
Neuropil
In neuroanatomy, a neuropil, which is sometimes referred to as a neuropile, is a region between neuronal cell bodies in the gray matter of the brain and blood-brain barrier . It consists of a dense tangle of axon terminals, dendrites and glial cell processes...
threads.
Aluminum
The idea that there is a link between aluminum exposure and the formation of neurofibrillary tangles has floated around the scientific community for sometime without having been definitively proven or disregarded. Recently a study examining the hippocampal CA1 cells from individuals with and with out Alzheimer’s disease showed a small portion of the pyramidal cells contain cytoplasmic pools within their somasSomàs
Sornàs is a village in Andorra, located in the parish of Ordino....
containing early NFTs. These cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to mature NFTs. (Walton) While a connection between aluminum and NFTs and AD is maintained, there is evidence that aluminum does not directly cause the formation of NFTs or AD.
Pathology
It has been shown that the degree of cognitive impairment in diseases such as AD is significantly correlated with the presence of neurofibrillary tangles.Harmful or Protective?
There has been some suggestion that the formation of NFTs is not a causal relationship with disease. Rather that NFTs may be produced in response to a variety of conditions and may in fact be a compensatory response against oxidative stressOxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
and serves a protective function. Several points are made to argue the position that NFTs are perhaps protective instead of harmful. First there appears to be a dispute as to the impact of neurofibrillary tangles on neuronal viability because some neurons containing NFTs survive for decades. Furthermore, NFTs have been found in apparently healthy individuals, indicating that NFTs are not directly related to neural degeneration
Degeneration
The idea of degeneration had significant influence on science, art and politics from the 1850s to the 1950s. The social theory developed consequently from Charles Darwin's Theory of Evolution...
. It has been proposed that the formation of NFTs is part of a multifaced compensatory response where oxidative insult activates several kinases, which are then capable of phosphorylating tau. This then prompts the early formation of NFTs, which reduce oxidative damage and prolong the function of the neuron. While an intriguing theory, scientists have not come to a firm conclusion as to what role NFTs play in neurodegenerative diseases.
Neuron loss
Traditionally believed to play a major role in neuron loss, NFTs are an early event in pathologies such as Alzheimer’s disease, and as more NFTs form, there is substantially more neuron loss. However, it has been shown that there is significant neuron loss before the formation of neurofibrillary tangles, and that NFTs account for only a small proportion (around 8.1%) of this neuron loss. Coupled with the longevity of neurons containing NFTs, it is likely that some other factor is primarily responsible for the bulk of neuron loss in these diseases, not the formation of neurofibrillary tangles.NFT-predominant dementia vs. Classical Alzheimer’s
It is currently unclear as to whether or not Neurofibrillary tangle-predominant dementia (NFTPD) (a.k.a. tangle-only dementia) is a variant of the traditional Alzheimer’s disease, or a genetically distinct entity. Characterized by later onset and milder cognitive impairment, the distribution of NFT pathology is more closely related to that found in centenarians showing no or limited cognitive impairment. NFTs are generally limited to allocortical/limbic regions of the brain with limited progression to the neocortexNeocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
but a greater density in the allocortical/hippocampal region. Plaques are generally absent.
Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB)
The degree of NFT involvement in AD is defined by BraakBraak
Braak is a municipality in the district of Stormarn, in Schleswig-Holstein, Germany....
stages. Braak stages I and II are used when NFT involvent is confined mainly to the transentorhinal region of the brain. Stages III and IV indicated involvement of limbic regions such as the hippocampus, and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.
Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, however, neocortical NFT scores show markedly different patterns between AD+DLB and Classical Alzheimers. In pure AD, NFT are predominately found at a high frequency: In AD+DLB, the distribution of NFT frequency was found to be bimodal: NFTs were either frequent or few to absent. Additionally, neocortical NFT frequency in the AD+DLB group tended to parallel the severity of other types of tau cytopathology
Cytopathology
Cytopathology is a branch of pathology that studies and diagnoses diseases on the cellular level. The discipline was founded by Rudolf Virchow in 1858. A common application of cytopathology is the Pap smear, used as a screening tool, to detect precancerous cervical lesions and prevent cervical...
.
Link to Aggression and Depression In Alzheimer's Patients
A recent study looked for correlation between the quantitative aspects of Alzheimer's disease (neuron loss, neuritic plaque and neurofibrillary tangle load) and aggression frequently found in Alzheimer's patients. It was found that only an increase in neurofibrillary tangle load was associated with severity of aggression and chronic aggression in Alzheimer's patients. While this study does indicate a correlationCorrelation
In statistics, dependence refers to any statistical relationship between two random variables or two sets of data. Correlation refers to any of a broad class of statistical relationships involving dependence....
between NFT load and severity of aggression, it does not provide a causative
Causative
In linguistics, a causative is a form that indicates that a subject causes someone or something else to do or be something, or causes a change in state of a non-volitional event....
argument.
Research has also indicated that patients with AD and comorbid depression show higher levels of neurofibrillary tangle formation than individuals with AD but no depression. Comorbid depression increased the odds for advanced neuropathologic disease stage even when controlling for age, gender, education and cognitive function.
Statins
Statins have been shown to reduce the neurofibrillary tangle burden in mouse models, likely due to their anti-inflammatoryAnti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
capacities.
Cyclin-dependent kinase 5
Cyclin-dependent kinase 5Cyclin-dependent kinase 5
Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5 gene. The protein encoded by this gene is part of the cyclin-dependent kinase family.-Physiological Role:...
(CDK5) is a kinase that has been previously hypothesized to contribute to tau pathologies. RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
(RNAi) mediated silencing of the CDK5 gene has been proposed as a novel therapeutic strategy again tau pathology, such as neurofibrillary tangles. Knockdown
Knockdown
Knockdown may refer to:*"Knockdown" , a song by Alesha Dixon* Knockdown, in full-contact combat sports, when a fighter is down or vulnerable, often preliminary to a knockout...
of CDK5 has been shown to reduce the phosphorylation of tau in primary neuronal cultures and in mouse models. Furthermore, this silencing showed a dramatic reduction in the number of neurofibrillary tangles.
Lithium
Lithium has been shown to decrease the phosphorylation of tau. Lithium treatment has been shown to reduce the density of neurofibrillary tangles in transgenic models in the hippocampus and spinal cordSpinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. Despite the decrease in density of NFTs, motor and memory deficits were not seen to improve following treatment. Additionally, no preventative effects have been seen in patients undergoing lithium treatment.
Other conditions
- Progressive supranuclear palsyProgressive supranuclear palsyProgressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....
although with straight filament rather than PHF tau - Dementia pugilisticaDementia pugilisticaDementia pugilistica is a type of neurodegenerative disease or dementia, which may affect amateur or professional boxers as well as athletes in other sports who suffer concussions...
(chronic traumatic encephalopathy) - Frontotemporal dementia and parkinsonism linked to chromosome 17Frontotemporal dementia and parkinsonism linked to chromosome 17Frontotemporal dementia and parkinsonism linked to chromosome 17 is an autosomal dominant neurodegenerative disorder, which has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference...
however without detectable β-amyloid plaques. - Lytico-Bodig diseaseLytico-Bodig diseaseLytico-Bodig disease, sometimes spelled Lytigo-bodig is a neurological disease of uncertain aetiology that exists in the United States territory of Guam....
(Parkinson-dementia complex of Guam) - GangliogliomaGangliogliomaGanglioglioma is a tumour that arises from ganglion cells in the central nervous system.The term "gangliocytoma" is sometimes equated with ganglioglioma. However, it is also sometimes equated with ganglioneuroma. In this context, the glial nature of the tumor is de-emphasized...
and gangliocytoma - Meningioangiomatosis
- Subacute sclerosing panencephalitisSubacute sclerosing panencephalitisSubacute sclerosing panencephalitis is a rare chronic, progressive encephalitis that affects primarily children and young adults, caused by a persistent infection of immune resistant measles virus . No cure for SSPE exists, but the condition can be managed by medication if treatment is started at...
- As well as lead encephalopathy, tuberous sclerosisTuberous sclerosisTuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
, Hallervorden-Spatz disease, and lipofuscinosis
External links
- Pathologic page about Neurofibrillary tangles, by the University of Oklahoma.
- http://www.termedia.pl/magazine.php?magazine_id=20&article_id=5368&magazine_subpage=ABSTRACT
- http://www.lifesci.sussex.ac.uk/home/Julian_Thorpe/ad_cyto.htm#tau
- It Takes Tau to Tangle : Plaques, Tangles and Neurodegenerative Disease (requires Flash video software)
- The Truth about Neurofibrillary Tangles (Flash video)
- Neurofibrillary Tangles - a definition (Flash video)
- Neurofibrillary Tangles in Alzheimer's Disease (Flash video)