thumb|Microscopy of a cell with neurofibrillary tangles (marked by arrows)

Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. NFTs also are present in numerous other diseases known collectively as tauopathies. Little is known about their exact relationship to the different pathologies, but it is typically recognized that tauopathy is an important factor in the pathogenesis of several neurodegenerative diseases.

NFTs consist primarily of a misfolded, hyperphosphorylated microtubule-associated protein known as tau, which abnormally polymerizes into insoluble filaments within cells. Under the electron microscope, these polymers of tau are seen to take two basic forms: paired helical filaments (PHFs) and straight filaments. These basic types of tau filaments can vary structurally, especially in different tauopathies. The role of hyperphosphorylation in this process is uncertain. One possibility is that hyperphosphorylation reduces the normal binding of tau to microtubules, freeing the protein to self-assemble into polymers, but as of 2024, Michel Goedert and colleagues stated that "It is unknown if phosphorylation is necessary and/or sufficient for the assembly of tau into filaments in the brain". At stage 0 there are morphologically normal pyramidal cells showing diffuse or fine granular cytoplasmic staining with anti-tau antibodies (in other words, the cells appear to be healthy with minimal presence of aberrant tau); at stage 1 some delicate, elongated inclusions are stained by antibodies to tau (these are early tangles); stage 2 is represented by the classic appearance of NFTs as seen with anti-tau immunostaining; stage 3 is exemplified by ghost tangles (tangles outside of cells where the host neuron has died), which are characterized by a reduced immunostaining for tau but marked immunostaining for ubiquitin. Once formed, NFTs appear to last for a long time in the brain, possibly remaining for many years after the death of the neurons in which they are formed.

Causes

thumb|right|upright|Hypothetical illustration of how microtubules disintegrate with Alzheimer's disease

Genetics

In adult humans there are 6 different types ("isoforms") of tau protein. The different tau isoforms range from 352 to 441 amino acids in length, and they influence the type of neurofibrillary pathology that is present in different tauopathies. An important segment of tau that regulates its binding to microtubules and also its anomalous self-assembly into fibrils is the repeat domain that consists of stretches of recurring amino acids; the repeat domain in tau contains either 3 or 4 Repeats (forming what are called "3R tau" and "4R tau"). There are also two different inserts in the amino terminal part of tau, whose presence or absence - along with either 3 or 4 repeats - define the 6 tau isoforms. In cases of severe, acute traumatic brain injury, the protein amyloid beta (Aβ) (which is associated with amyloid plaques) can accumulate in the brain, often in the absence of tauopathy;

The distribution of tau pathology in CTE differs from that in other neurodegenerative disorders such as Alzheimer's disease. and it is well known to be neurotoxic in high doses. It is the most ubiquitous metal in the earth's crust, so it is rather hard to avoid; the most common sources of aluminium exposure in humans are food, drinking water, and inhalation (aluminium exposure via vaccines is negligible). Aluminium has been largely eliminated from dialysis treatments, so that today the risk of encephalopathy has been greatly reduced. Studies have detected aluminium in tangle-bearing neurons from Alzheimer patients, but it is not certain if the aluminium caused the tangles or simply binds to them, and the idea that aluminium is a cause of Alzheimer's disease per se has failed to gain wide acceptance in the field. Given the current state of knowledge, it is reasonable to conclude that excessive aluminium is toxic to the brain, that it can cause seizures and dementia, and that it can induce abnormalities in neurons, but it does not appear to engender the neurofibrillary tangles that characterize naturally occurring human neurodegenerative disorders such as Alzheimer's disease.

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.

It is currently unclear as to whether or not primary age-related tauopathy (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 showing no or limited cognitive impairment. NFTs are generally limited to allocortical/limbic regions of the brain with limited progression to the neocortex 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 transentorhinal 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.

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.

Cyclin-dependent kinase 5

Cyclin-dependent kinase 5 (CDK5) is a kinase that has been previously hypothesized to contribute to tau pathologies. RNA interference (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 Alzheimer's disease, 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. although with straight filament rather than PHF tau

  • Dementia pugilistica (chronic traumatic encephalopathy)
  • Frontotemporal dementia and parkinsonism linked to chromosome 17 however without detectable β-amyloid plaques.
  • Lytico-Bodig disease (Parkinson-dementia complex of Guam)
  • Ganglioglioma and gangliocytoma
  • Meningioangiomatosis
  • Subacute sclerosing panencephalitis
  • As well as lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, and lipofuscinosis

See also

  • Proteopathy

References

  • 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
  • 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)

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