Humpath.com - Human pathology

Home > E. Pathology by systems > Nervous system > Central nervous system > neurofibrillary tangles

neurofibrillary tangles

Friday 18 January 2008

Neurofibrillary tangles (NFTs) , tau tangles; globose tangles

Definition: Neurofibrillary tangles (NFTs) are aggregations of paired helical filaments or straight filaments, composed predominantly of hyperphosphorylated tau (MAPT) (tau tangles). They are present in the brain of individuals with Alzheimer disease (AD) and other neurodegenerative diseases classed as tauopathies.

Images

- globose tangles in PSP case (substantia nigra ). Immuno is tau .

Neurofibrillary tangles are filamentous inclusions that accumulate in selective neurons in the brains of individuals with Alzheimer disease, but they also occur in other neurodegenerative disorders, including frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

The major component of neurofibrillary tangles is the microtubule-associated protein tau (MAPT). In its normal state, tau is a soluble protein that promotes microtubule assembly and stabilization.

Pathological tau protein, by contrast, exhibits altered solubility properties, forms filamentous structures and is abnormally phosphorylated at certain residues. It has been shown that phosphorylated tau has reduced affinity for microtubules.

NFTs are intracellular fibrillar structures composed of aggregations of paired helical filaments (PHFs), which are made up of abnormally phosphorylated tau (TAU).

Tau filaments accumulate in dystrophic neurites as fine neuropil threads or as bundles of PHFs in neuronal bodies, forming neurofibrillary tangles (NFTs) which become "extracellular ghost tangles" after the death of the neurons.

The number and localization of NFTs has been correlated with the level of dementia; by contrast, such a correlation has not been demonstrated for senile plaques.

Pathology

Neurofibrillary tangles are filamentous inclusions that accumulate in selective neurons in the brains of individuals with AD, but they also occur in other neurodegenerative disorders, including frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

The major component of tangles is the microtubule-associated protein tau (MATP). In its normal state, tau is a soluble protein that promotes microtubule assembly and stabilization. Pathological tau protein, by contrast, exhibits altered solubility properties, forms filamentous structures and is abnormally phosphorylated at certain residues.

It has been shown that phosphorylated tau has reduced affinity for microtubules.

The tau protein is encoded by a single gene (MAPT) located on chromosome 17, although it is alternatively spliced to yield six major protein isoforms in the adult human brain. The tau gene contains 15 exons, and exons 2, 3 and 10 can be alternatively spliced. Four imperfect tandem repeats are encoded by exons 9–12. Therefore, the alternative splicing of exon 10 yields isoforms with either three or four repeat domains, referred to as 3R and 4R tau, depending if exon 10 is absent or present, respectively. Alternative splicing of exons 2 and 3 yields variants containing zero (0N), one (1N) or two (2N) inserts at the N-terminus, such that six tau isoforms are formed: 3R0N, 3R1N, 3R2N, 4R0N, 4R1N and 4R2N.

In the adult human brain, the proportion of 3R to 4R tau is 1:1, whereas in the adult mouse brain, 4R tau is the only tau isoform present 23 and 24. Tauopathies can be further classified based on whether tangles are composed of 3R or 4R tau isoforms.

For example, in AD, both 3R and 4R tau accumulate in neurofibrillary tangles; other disorders are marked by only 3R tau (e.g. Pick disease) or 4R tau (e.g. CBD and PSP).

In AD, tau pathology is restricted to neurons, but in certain other tauopathies, such as the 4R tauopathies CBD and PSP, tau inclusions are also observed in glia.

The gene encoding tau is not genetically linked to AD, but tau mutations cause FTDP-17. The identification of disease-causing mutations in tau establishes that tau dysfunction suffices to cause neurodegeneration.

The lack of genetic association to AD, however, further corroborates the evidence that tau lies downstream of Aβ in the neurodegenerative cascade. This should not imply that tau pathology is irrelevant or innocuous in the pathogenesis of AD, because neurodegeneration induced by tau dysfunction might have a pivotal role in AD.

This evidence further indicates that tau pathology can be triggered by different mechanisms, both dependent on and independent of Aβ.

Animal models

Generating mice with both plaques and tangles is crucial for studies of the molecular relationship between Aβ and tau and to test the effectiveness that anti-AD interventions have on both pathologies.

To make a model that better mimics AD neuropathology, a novel approach was used that involved co-microinjecting two transgenes (encoding APPswe and tauP301L under the control of the Thy1.2 promoter) into single-cell embryos harvested from PS1M146V KI mice.

The resulting mice are triple-transgenic mice (and referred to as 3xTg-AD mice). Because of the strategy used to generate the 3xTg-AD mice, the mice are on the same genetic background (thus avoiding an important confounding variable), they breed easily and efficiently (as easily as a single-transgenic mouse) and exist in both a hemizygous and homozygous genotype (enabling one to assess the effects of doubling gene expression on cognition in mice of the same genetic background).

The homozygous mice help to further reduce breeding and genotyping efforts because all resulting offspring will be triple transgenic (even if bred to a normal mouse).

The 3xTg-AD mice progressively develop Aβ and tau pathology (Figure 4), with a temporal- and region-specific profile that closely mimics pathological development in the human AD brain.

In spite of equivalent overexpression of the human βAPP and human tau transgenes, Aβ deposition develops before the tangle pathology, consistent with the amyloid-cascade hypothesis.

Whereas extracellular amyloid deposits manifest by six months of age, conformational changes in tau, as evidenced by MC1 immunostaining or immunoreactivity with phospho-specific tau markers, are not apparent until the mice are 10–12 months of age.

There is also a hierarchal pattern to the tau staining, with MC1 immunostaining emerging first, followed by phosphospecific markers, such as AT8 and AT180, and finally PHF-1 immunoreactivity.

These results indicate that, as in the AD brain, tau in the 3xTg-AD mice undergoes a conformational change detected by the MC1 antibody; this is assumed to be an early stage in the progression of the tau pathology. Subsequently, tau becomes hyperphosphorylated, indicative of a later stage of tau pathology.

Tau is normally phosphorylated at different amino acid residues; however, in pathological conditions, the amount of phosphorylation is greatly increased at specific sites, including Ser202 and Thr205 (recognized by AT8), Ser231 (recognized by AT180) and Ser396 and Ser404 (recognized by PHF-1).

Amyloid plaques and neurofibrillary tangles accumulate in a region- and age-dependent manner in the 3xTg-AD mice, most notably within the hippocampus, amygdala and cerebral cortex. Aβ plaques are first found to form in cortical areas and then accumulate in the hippocampus and amygdala.

Tau pathology is first apparent in the hippocampus, where it becomes localized to the somatodendritic compartment, rather than in the axons. Subsequently, the tau protein is hyperphosphorylated and becomes immunoreactive with antibodies such as AT-8.

Animal models

- tauopathy in Drosophila: neurodegeneration without NFTs

See also

- intraneuronal protein aggregates