Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

that are most commonly known as a primary

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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

hyperphosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

of a

microtubule-associated protein In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to the stability of the cell and its internal structures and the transport of components withi ...

known as

tau Tau (; uppercase Τ, lowercase τ or \boldsymbol\tau; ) is the nineteenth letter of the Greek alphabet, representing the voiceless alveolar plosive, voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300 ...

, 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 filament Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary t ...

s"). The precise mechanism of tangle formation is not completely understood, though it is typically recognized that tangles are a primary causative factor in neurodegenerative disease.

Cytoskeletal changes

Three different maturation states of NFT have been defined using anti-tau and anti-

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

immunostaining In biochemistry, immunostaining is 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 ...

. At stage 0 there are morphologically normal

pyramidal cell Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cort ...

s showing diffuse or fine granular

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

staining with anti-tau. In other words, cells are healthy with minimal tau presence; at stage 1 some delicate elongate inclusions are stained by tau

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

(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 A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

has died), which are characterized by a reduced anti-tau but marked anti-ubiquitin immunostaining.

Causes

upDiagram of how microtubules disintegrate with Alzheimer's disease

Mutated tau

The traditional understanding is that tau binds to

microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

and assists with their self-assembly, 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 acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

residues. These lesions, over time, develop into filamentous interneuronal neurofibrillary 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 In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

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 in the

vector Vector most often refers to: * Euclidean vector, a quantity with a magnitude and a direction * Disease vector, an agent that carries and transmits an infectious pathogen into another living organism Vector may also refer to: Mathematics a ...

saw increased tau expression, as early as 3 weeks after vector injection, which was measured using a

Western blot The western blot (sometimes called the protein immunoblot), or western blotting, is a widely used analytical technique in molecular biology and immunogenetics to detect specific proteins in a sample of tissue homogenate or extract. Besides detect ...

. 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 An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...

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 Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...

, following

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...

(TBI), may increase tau

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

. 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 neurodegenerative disease

chronic traumatic encephalopathy Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets wor ...

(CTE), previously called

dementia pugilistica Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets worse ...

, is highly associated with NFTs and

neuropil Neuropil (or "neuropile") is any area in the nervous system composed of mostly unmyelinated axons, dendrites and glial cell processes that forms a synaptically dense region containing a relatively low number of cell bodies. The most prevalent ...

threads.

Aluminium

The idea that there is a link between

aluminium Aluminium (or aluminum in North American English) is a chemical element; it has chemical symbol, symbol Al and atomic number 13. It has a density lower than that of other common metals, about one-third that of steel. Aluminium has ...

exposure and the formation of neurofibrillary tangles has floated around the scientific community for some time without having been definitively proved or disregarded. Recently a study examining the

hippocampal The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...

CA1 cells from individuals with and without Alzheimer's disease showed a small portion of the pyramidal cells contain

pools within their somas containing early NFTs. These cytoplasmic pools are aggregates of an aluminium/hyperphosphorylated tau complex similar to mature NFTs. (Walton) While a connection between aluminium and NFTs and AD is maintained, there is evidence that aluminium does not directly cause the formation of NFTs or AD. However it is claimed that chronic aluminium intake can cause Alzheimer's by disrupting the microtubules in the filaments.

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.

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.

Primary age-related tauopathy vs. classical Alzheimer's

It is currently unclear as to whether or not

primary age-related tauopathy Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur ...

(PART), a term in which includes some cases formerly referred to as neurofibrillary tangle-predominant dementia (NFTPD) or tangle-only dementia, is a variant of the traditional Alzheimer's disease, or a distinct entity. Characterized by later onset and milder cognitive impairment, the distribution of NFT pathology is more closely related to that found in

centenarians A centenarian is a Human, person who has Ageing, reached the age of 100. Because life expectancy, life expectancies at birth worldwide are well below 100, the term is invariably associated with longevity. The United Nations estimated that there w ...

showing no or limited cognitive impairment. NFTs are generally limited to allocortical/

limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

regions of the brain with limited progression to the

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

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 Braak staging. Braak stages I and II are used when NFT involvement is confined mainly to the trans entorhinal region of the brain. Stages III and IV are indicated when there is 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 Alzheimer's. In pure AD, NFT are predominantly 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 (from Greek , ''kytos'', "a hollow"; , ''pathos'', "fate, harm"; and , ''-logia'') is a branch of pathology that studies and diagnoses diseases on the cellular level. The discipline was founded by George Nicolas Papanicolaou in ...

Link to aggression and depression in people living with Alzheimer's disease

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

correlation In statistics, correlation or dependence is any statistical relationship, whether causal or not, between two random variables or bivariate data. Although in the broadest sense, "correlation" may indicate any type of association, in statistics ...

between NFT load and severity of aggression, it does not provide a

causative In linguistics, a causative (abbreviated ) is a valency-increasing operationPayne, Thomas E. (1997). Describing morphosyntax: A guide for field linguists'' Cambridge: Cambridge University Press. p. 173–186. that indicates that a subject either ...

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.

Treatment

Statins

Statins Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

have been shown to reduce the neurofibrillary tangle burden in mouse models, likely due to their

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

capacities.

Cyclin-dependent kinase 5

Cyclin-dependent kinase 5 (CDK5) is a kinase that has been previously hypothesized to contribute to tau pathologies.

RNA interference RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...

(RNAi) mediated silencing of the CDK5 gene has been proposed as a novel therapeutic strategy against tau pathology, such as neurofibrillary tangles. Knockdown 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. However, in conditions such as

, only about 1% is hereditary, and therefore RNAi therapy may be inadequate for addressing the needs of the majority of those who have this disease.

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 cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. Despite the decrease in density of NFTs, motor and memory deficits were not seen to improve following treatment. Additionally, no preventive effects have been seen in patients undergoing lithium treatment.

Curcumin

Curcumin Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...

has been shown to reduce memory deficit and tau monomers in animal models, however no clinical trials have shown curcumin to remove tau from the brain.

Other conditions

Progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

although with straight filament rather than PHF tau *

Dementia pugilistica Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets worse ...

(chronic traumatic encephalopathy) *

Frontotemporal dementia and parkinsonism linked to chromosome 17 Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative tauopathy and Parkinson plus syndrome. FTDP-17 is caused by mutations in the MAPT (microtubule associated protein tau) gene l ...

however without detectable β-amyloid plaques. *

Lytico-Bodig disease Lytico-Bodig (also Lytigo-bodig) disease, Guam disease, amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), and Western Pacific amyotrophic lateral sclerosis-parkinsonism-dementia complex is a rare, terminal neurodegenerative dis ...

(Parkinson-dementia complex of Guam) *

Ganglioglioma A ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults. They are mixed cell tumors containing both neural ganglionic cells and neural gli ...

and

gangliocytoma A ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults. They are mixed cell tumors containing both neural ganglionic cells and neural gli ...

Meningioangiomatosis Meningioangiomatosis is a rare disease and tauopathy of the brain. It is characterized by a benign lesion of the leptomeninges usually involving the cerebral cortex, and by leptomeningeal and meningovascular proliferation. Often the patient wi ...

Subacute sclerosing panencephalitis Subacute sclerosing panencephalitis (SSPE), also known as Dawson disease, is a rare form of progressive brain inflammation caused by a persistent infection with the measles virus. The condition primarily affects children, teens, and young adults ...

*As well as lead encephalopathy,

tuberous sclerosis Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combinatio ...

, Pantothenate kinase-associated neurodegeneration, and lipofuscinosis

References

External links

Pathologic page about Neurofibrillary tangles
{{Webarchive, url=https://web.archive.org/web/20150924062517/http://www.oumedicine.com/body.cfm?id=2881 , date=2015-09-24 , by the University of Oklahoma. * http://www.termedia.pl/magazine.php?magazine_id=20&article_id=5368&magazine_subpage=ABSTRACT *https://web.archive.org/web/20051028184424/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) Alzheimer's disease Neuropathology