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 problem ...

tau protein The tau proteins (abbreviated from tubulin associated unit) are 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 maintaining ...

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 neurodegeneration, 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 short-term me ...

. Their presence is also found in numerous other diseases known as

tauopathies 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 ...

. Little is known about their exact relationship to the different pathologies.

Formation

Neurofibrillary tangles are formed by

hyperphosphorylation 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 ...

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 within ...

known as

tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...

, 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, 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 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 1980s. Fo ...

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 A ...

. 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 neurons are the primary excitation units of the mammalian prefrontal cor ...

s 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. Th ...

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 the ...

(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. N ...

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

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 (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 ba ...

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

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 accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

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, vag ...

, 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 TBI/concussionto severe traumatic b ...

(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 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 o ...

(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 o ...

, 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 anat ...

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 The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...

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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

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 In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

, 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 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 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 person who has reached the age of 100 years. Because life expectancies worldwide are below 100 years, the term is invariably associated with longevity. In 2012, the United Nations estimated that there were 316,600 living centen ...

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. ''Ps ...

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 The entorhinal cortex (EC) is an area of the brain's allocortex, located in the medial temporal lobe, whose functions include being a widespread network hub for memory, navigation, and the perception of time.Integrating time from experience in the ...

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 mi ...

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 1 ...

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, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...

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 or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

capacities.

Cyclin-dependent kinase 5

Cyclin-dependent kinase 5 Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS). The molecule belongs ...

(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 o ...

(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 spi ...

. 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 ...

(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 Progressive supranuclear palsy (PSP) is a late-onset degenerative 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 ...

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 o ...

(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 loca ...

however without detectable β-amyloid plaques. *

Lytico-Bodig disease Lytico-bodig (also Lytigo-bodig) disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC) is a neurodegenerative disease of uncertain etiology endemic to the Chamorro people of the island of Guam in Micronesia. ''Ly ...

(Parkinson-dementia complex of Guam) *

Ganglioglioma 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 Classification Gangliogliomas are generally benign WHO grade I tumors; the presence o ...

and

gangliocytoma 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 Classification Gangliogliomas are generally benign WHO grade I tumors; the presence o ...

*Meningioangiomatosis *

Subacute sclerosing panencephalitis Subacute sclerosing panencephalitis (SSPE)—also known as Dawson disease—is a rare form of chronic, progressive brain inflammation caused by slow infection with certain defective strains of hypermutated measles virus. The condition primarily ...

*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 e ...

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 combination ...

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

References

{{Reflist, 2, refs={{cite journal , author1=Lee H. G. , author2=Perry G. , author3=Moreira P. I. , author4=Garrett M. R. , author5=Liu Q. , author6=Zhu X. W. , year = 2005 , title = Tau phosphorylation in Alzheimer's disease: pathogen or protector? , journal = Trends in Molecular Medicine , volume = 11 , issue = 4, pages = 164–169 , doi = 10.1016/j.molmed.2005.02.008 , pmid = 15823754 , display-authors=etal, hdl=10316/4769 , hdl-access = free {{cite journal , author1=Leroy K. , author2=Ando K. , author3=Heraud C. , author4=Yilmaz Z. , author5=Authelet M. , author6=Boeynaems J. M. , year = 2010 , title = Lithium Treatment Arrests the Development of Neurofibrillary Tangles in Mutant Tau Transgenic Mice with Advanced Neurofibrillary Pathology , url = http://www.j-alz.com/issues/19/leroy_supplement.pdf , journal = Journal of Alzheimer's Disease , volume = 19 , issue = 2, pages = 705–719 , pmid=20110614 , doi=10.3233/JAD-2010-1276, display-authors=etal {{cite journal , vauthors=Ma QL, Zuo X, Yang F, Ubeda O, Gant D, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P, Teter B, Cole GM, Frautschy SA , year = 2012 , title = Curcumin suppresses soluble tau oligomers and corrects molecular chaperone, synaptic and behavioral deficits in aged human tau transgenic mice. , journal = Journal of Biological Chemistry , pmid=23264626 , doi=10.1074/jbc.M112.393751 , volume=288 , issue=6 , pages=4056–65 , pmc=3567657, doi-access = free {{cite journal , author1=Klein R. L. , author2=Lin W. L. , author3=Dickson D. W. , author4=Lewis J. , author5=Hutton M. , author6=Duff K. , year = 2004 , title = Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau , journal = American Journal of Pathology , volume = 164 , issue = 1, pages = 347–353 , doi = 10.1016/S0002-9440(10)63124-0 , pmid = 14695347 , pmc = 1602230 , display-authors=etal {{cite journal , author1=Lai M. K. P. , author2=Chen C. P. , author3=Hope T. , author4=Esiri M. M. , year = 2010 , title = Hippocampal neurofibrillary tangle changes and aggressive behaviour in dementia , journal = NeuroReport , volume = 21 , issue = 17, pages = 1111–1115 , doi = 10.1097/WNR.0b013e3283407204 , pmid = 20890229 , s2cid=14317916 {{cite journal , author1=Rapp M. A. , author2=Schnaider-Beeri M. , author3=Purohit D. P. , author4=Perl D. P. , author5=Haroutunian V. , author6=Sano M. , year = 2008 , title = Increased neurofibrillary tangles in patients with Alzheimer disease with comorbid depression , journal = American Journal of Geriatric Psychiatry , volume = 16 , issue = 2, pages = 168–174 , doi = 10.1097/JGP.0b013e31816029ec , pmid = 18239198 {{cite journal , year = 2016 , title = Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice , journal = Science , volume = 354 , issue = 6314, pages = 904–908 , pmid = 27856911 , last1 = Ittner , first1 = A , last2 = Chua , first2 = S. W. , last3 = Bertz , first3 = J , last4 = Volkerling , first4 = A , last5 = Van Der Hoven , first5 = J , last6 = Gladbach , first6 = A , last7 = Przybyla , first7 = M , last8 = Bi , first8 = M , last9 = Van Hummel , first9 = A , last10 = Stevens , first10 = C. H. , last11 = Ippati , first11 = S , last12 = Suh , first12 = L. S. , last13 = MacMillan , first13 = A , last14 = Sutherland , first14 = G , last15 = Kril , first15 = J. J. , last16 = Silva , first16 = A. P. , last17 = MacKay , first17 = J , last18 = Poljak , first18 = A , last19 = Delerue , first19 = F , last20 = Ke , first20 = Y. D. , last21 = Ittner , first21 = L. M. , doi = 10.1126/science.aah6205 , bibcode = 2016Sci...354..904I , doi-access = free

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
(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