Neurofibrillary tangle

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Microscopy of a cell with neurofibrillary tangles (marked by arrows) Histopathology of neurofibrillary tangles in Alzheimer's disease - annotated.jpg
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. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.

Contents

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 filaments"). 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.[ citation needed ]

Cytoskeletal changes

Three different maturation states of NFT have been defined using anti-tau and anti-ubiquitin immunostaining. At stage 0 there are morphologically normal pyramidal cells 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 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 has died), which are characterized by a reduced anti-tau but marked anti-ubiquitin immunostaining. [1]

Causes

Diagram of how microtubules disintegrate with Alzheimer's disease TANGLES HIGH.jpg
Diagram of how microtubules disintegrate with Alzheimer's disease

Mutated tau

The traditional understanding is that tau binds to microtubules 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. [2] More explicitly, intracellular lesions known as pretangles develop when tau is phosphorylated excessively and on improper amino acid 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 adult mice. This experiment resulted in the formation of neurofibrillary tangles and pretangle formations. [3] The human mutant P301 tau gene is associated with frontotemporal dementia 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. [4] 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. [4] 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. [4]

Traumatic brain injury

Preliminary research indicates that iron deposits due to hemorrhaging, following traumatic brain injury (TBI), may increase tau pathology. 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. [5] NFTs are most commonly seen associated with repetitive mild TBI as opposed to one instance of severe traumatic brain injury. [6] 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 cytoplasmic pools within their somas containing early NFTs. These cytoplasmic pools are aggregates of an aluminium/hyperphosphorylated tau complex similar to mature NFTs. (Walton)[ specify ] 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. [7] However it is claimed that chronic aluminium intake can cause Alzheimer's by disrupting the microtubules in the filaments. [8] [9]

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. [10]

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. [11] 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. [12] [13]

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. [14]

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. [15]

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. [16] While this study does indicate a correlation between NFT load and severity of aggression, it does not provide a causative 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. [17] Comorbid depression increased the odds for advanced neuropathologic disease stage even when controlling for age, gender, education and cognitive function. [17]

Treatment

Overview of RNA interference RNAi-simplified.svg
Overview of RNA interference

Statins

Statins have been shown to reduce the neurofibrillary tangle burden in mouse models, likely due to their anti-inflammatory capacities. [18]

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. [19]

Lithium

Lithium has been shown to decrease the phosphorylation of tau. [20] Lithium treatment has been shown to reduce the density of neurofibrillary tangles in transgenic models in the hippocampus and spinal cord. 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. [20]

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. [21]

Other conditions

See also

Related Research Articles

<span class="mw-page-title-main">Dementia with Lewy bodies</span> Type of progressive dementia

Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described by Kenji Kosaka in 1976.

<span class="mw-page-title-main">Lewy body</span> Spherical inclusion commonly found in damaged neurons

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

<span class="mw-page-title-main">Progressive supranuclear palsy</span> Medical condition

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment. PSP may be mistaken for other types of neurodegeneration such as Parkinson's disease, frontotemporal dementia and Alzheimer's disease. The cause of the condition is uncertain, but involves the accumulation of tau protein within the brain. Medications such as levodopa and amantadine may be useful in some cases.

<span class="mw-page-title-main">Tau protein</span> Group of six protein isoforms produced from the MAPT gene

The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid 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 microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Tauopathy</span> Medical condition

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 as tau, causing the protein to dissociate from microtubules and form insoluble aggregates. The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimer's disease or play a peripheral role is unknown.

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<span class="mw-page-title-main">Chronic traumatic encephalopathy</span> Neurodegenerative disease caused by head injury

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Heiko Braak is a German anatomist. Braak was born in Kiel, Schleswig-Holstein, and studied medicine at the universities of Hamburg, Berlin, and Kiel. He was Professor at the Institute of Clinical Neuroanatomy, Johann Wolfgang Goethe-University, Frankfurt am Main. Currently he is based at the 'Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Germany.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is 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 with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

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<span class="mw-page-title-main">Cholinergic neuron</span> Type of nerve cell

A cholinergic neuron is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic. Cholinergic neurons provide the primary source of acetylcholine to the cerebral cortex, and promote cortical activation during both wakefulness and rapid eye movement sleep. The cholinergic system of neurons has been a main focus of research in aging and neural degradation, specifically as it relates to Alzheimer's disease. The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in Alzheimer's disease.

<span class="mw-page-title-main">Synucleinopathy</span> Medical condition

Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells. There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies. Additionally, autopsy studies have shown that around 6% of sporadic Alzheimer's Disease exhibit α-synuclein positive Lewy pathology, and are sub-classed as Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD/ALB).

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<span class="mw-page-title-main">Experimental models of Alzheimer's disease</span>

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<span class="mw-page-title-main">Granulovacuolar degeneration</span>

Granulovacuolar degeneration refers to the occurrence within neurons of abnormal, fluid-filled bubbles (vacuoles) containing a dense proteinaceous granule. Granulovacuoles occur most commonly in pyramidal neurons of the hippocampus. They are present in small numbers in non-demented elderly people, but increase in frequency in Alzheimer's disease and other tauopathies. In Alzheimer's disease, granulovacuoles proliferate stage-wise in different brain areas, and their prevalence is correlated with the degree of tauopathy, Abeta plaque pathology, and cerebral amyloid angiopathy. Immunohistochemical analyses have found that the inner granule includes several proteins, including tubulin tau protein, TDP-43 and others. Although granulovacuoles and their functional significance are still poorly understood, they have been compared to autophagic vacuoles

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

References

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