Histopathology of neurofibrillary tangles in Alzheimer's disease - annotated

Neurofibrillary tangles (NFTs) are aggregates of

hyperphosphorylated Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signaling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems ...

tau protein that are most commonly known as a primary biomarker of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. 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 of a microtubule-associated protein 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 filament Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known a ...

s"). 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- ubiquitin

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 cells showing diffuse or fine granular

cytoplasmic In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

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), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...

(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, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

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 a ...

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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

residues. These lesions, over time, develop into

filamentous The word filament, which is descended from Latin ''filum'' meaning " thread", is used in English for a variety of thread-like structures, including: Astronomy * Galaxy filament, the largest known cosmic structures in the universe * Solar filamen ...

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 (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

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 disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

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 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 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 injury (TBI), may increase tau

pathology Pathology is the study of the causes and effects of disease or injury. 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 ...

. 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 (CTE), previously called dementia pugilistica, is highly associated with NFTs and neuropil threads.

Aluminium

The idea that there is a link between aluminium 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 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.

Harmful or protective?

There has been some suggestion that the formation of NFTs does not have 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 stress 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. It has been proposed that the formation of NFTs is part of a multifaceted 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 the theory is intriguing, scientists have not come to a firm conclusion as to what role NFTs play in neurodegenerative diseases. Results from the new study suggest that a specific phosphorylation of tau (at threonine-205) has a protective effect on neurons in a mouse model of excitotoxic, amyloid beta toxicity. The authors suggest that the reason tau becomes modified is to protect from damage caused by amyloid protein aggregation. A protein called kinase p38γ phosphorylates tau at the threonine-205 amino acid. The activity of this gamma kinase enzyme is mostly lost as Alzheimer Disease progresses, suggesting a loss of this protective effect. Reintroducing p38γ and increasing its activity prevented memory deficits from occurring in their mouse model, suggesting this enzyme as a potential target for future therapies. However increasing the activity of kinases has been shown to be difficult).

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 (PART), a term 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 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, sp ...

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 staging refers to two methods used to classify the degree of pathology in Parkinson's disease and Alzheimer's disease. These methods are used both in research and for the clinical diagnosis of these diseases and are obtained by performing ...

. 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 Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mic ...

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.

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 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 have been shown to reduce the neurofibrillary tangle burden in mouse models, likely due to their anti-inflammatory 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 (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, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...

. 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 (as Longvida) 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 although with straight filament rather than PHF tau * Dementia pugilistica (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 locat ...

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 Toxic encephalopathy is a neurologic disorder caused by exposure to neurotoxic organic solvents such as toluene, following exposure to heavy metals such as manganese, as a side effect of melarsoprol treatment for African trypanosomiasis, adverse ...

, tuberous sclerosis,

Pantothenate kinase-associated neurodegeneration Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden–Spatz syndrome, is a genetic degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in P ...

, and

lipofuscinosis Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These l ...

References

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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 *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
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The Truth about Neurofibrillary Tangles
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Neurofibrillary Tangles - a definition
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Neurofibrillary Tangles in Alzheimer's Disease
(Flash video) Alzheimer's disease Neuropathology