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PubMed1999

Neurons may live for decades with neurofibrillary tangles.

Neurons containing neurofibrillary tangles (NFT) are one of the pathological hallmarks of Alzheimer disease (AD). It is known that this population of neurons express gene products and thus function to some degree, but it is unknown how long these neurons may survive with NFT. It is also thought that the formation of NFT results in the death of neurons. Using quantitative data on neuron loss and NFT formation as a function of disease duration, we have generated a computer program that models both the degeneration of CA1 hippocampal neurons and the formation of NFT in these neurons in AD. Modeling various neuron survival times with NFT and altering selected assumptions upon which the models are based, we arrive at the conclusions that 1) CA1 hippocampal neurons survive with NFT for about 20 years, and 2) NFT may not be obligatory for death of CA1 hippocampal neurons in AD.

Aged↗
PubMed1995

Motor neuron disease with neurofibrillary tangles in a non-Guamanian patient.

Neurofibrillary tangles are described in Guamanian and post-encephalitic forms of motor neuron disease (MND) but not in sporadic MND. We report the neuropathological findings in a 79-year-old man who died after a 1-year history of MND without extrapyramidal features or dementia. There was no family history of neurological disease and he had not visited Guam. The spinal cord showed loss of anterior horn cells, and skeletal muscle typical changes of denervation. The brain appeared macroscopically normal but histology revealed many neurofibrillary tangles, particularly in medial temporal lobe structures, insula, nucleus basalis, hippocampus, oculomotor nucleus, raphe nuclei and locus ceruleus. Neurofibrillary tangles were not seen in the primary motor cortex, which appeared histologically unremarkable. Occasional tangles were present in the substantia nigra and pontine nuclei. None were seen in the cerebellum, medulla or spinal cord. The tangles were argyrophilic, and, in sections stained with thioflavin-S, both the intracellular and the extracellular tangles fluoresced strongly under ultraviolet light. The intracellular neurofibrillary tangles reacted strongly with an antibody to tau protein, and only occasional tangles showed weak ubiquitin immunoreactivity. Scattered neuropil threads were present in the cortex in the areas of neurofibrillary tangle formation. No plaques were present in any part of the brain and no A4/beta protein immunoreactivity was detected. Ultrastructural examination revealed Alzheimer-type neurofibrillary tangles composed of paired helical filaments. The present findings further extend the spectrum of diverse neurological disorders associated with neurofibrillary tangles.

Aged↗
PubMed2006

Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer's disease.

Neurofibrillary tangles are one of the neuropathological hallmark of Alzheimer's disease, described early as part of the pathological criteria of the disease. Ultrastuctural studies in the sixties showed their unusual features but their molecular composition was not unraveled before the mid-eighties. Initial biochemical studies suggested that they were composed of modified unidentified brain proteins, and several immunocytochemical studies suggested that they contained polypeptides cross-reactive with antibodies to cytoskeletal proteins. In 1985, we demonstrated that neurofibrillary tangles were immunolabelled by antibodies to the microtubule-associated protein tau and that antibodies raised to neurofibrillary tangles cross-reacted with tau proteins. These results were soon confirmed independently in several laboratories. Further studies were devoted to the analysis of tau post-translationnal modifications in the affected tissues and in cellular and animal models.

Alzheimer Disease↗
PubMed2002

Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice.

Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.

Animals↗
PubMed1981

Reappraisal of the fine structure of Alzheimer's neurofibrillary tangles.

Alzheimer's neurofibrillary tangles were studied by electron microscopy. The study includes four cases of Alzheimer's disease, two cases of atypical senile dementia, and one case of progressive supranuclear palsy. In Alzheimer's disease the tangles were composed of either straight filaments or paired helical filaments. In progressive supranuclear palsy the tangles were composed of 15 nm straight filaments or helical filaments. A few straight filaments were mixed with paired helical filaments. In atypical senile dementia, both straight and paired helical filaments comprised the tangles and one type of filaments appeared to intermingle with the other in the same neurons.

Adult↗
PubMed1998

The role of neurofibrillary tangles in Alzheimer disease.

The neuropathological diagnosis of Alzheimer disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangle formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurones, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenom. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network, and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still poorly understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully faithfully reproduce all the major cellular lesions of the disease.

Alzheimer Disease↗
PubMed1998

Ultrastructural aspects of neurofibrillary tangle formation in aging and Alzheimer's disease.

Neurofibrillary tangles, one of the neuropathological signs of Alzheimer's disease, are frequently present in brains of aged nondemented people. Ultrastructurally, neurofibrillary tangles appear as paired helical and straight filaments. Both types of filaments, made of hyperphosphorylated tau protein, are present in neurons with neurofibrillary tangles. Neurons with neurofibrillary tangles have been described to undergo an evolution, starting with the accumulation of hyperphosphorylated tau, followed by the progressive appearance of both types of filaments, and ending in the death of the neuron. We ultrastructurally studied this evolution, using immunocytochemistry with an antibody against phosphorylated tau protein, in both nondemented aged and Alzheimer's disease brains. No differences were found between nondemented and demented brains, thus indicating the occurrence of the same process in both cases. Our results also suggest that hyperphosphorylated tau protein first appears as granular material, which becomes organized into short and disordered paired helical filaments. These filaments elongate and gradually become arranged into bundles whose core regions are occupied by straight filaments.

Aged↗
PubMed2001

Plaque-like structures and arteriosclerotic changes in "diffuse neurofibrillary tangles with calcification" (DNTC).

"Diffuse neurofibrillary tangles with calcification" (DNTC) is a rare form of slowly progressive dementia characterized by temporal or fronto-temporal atrophy with neuronal loss and astrocytosis, neurofibrillary tangles and Fahr-type calcification, but no senile plaques in the cerebral cortex. In patients with DNTC, we detected a novel histopathological abnormality that we termed "plaque-like structures" (PLS). PLS appeared as oval, slightly eosinophilic masses of up to 100 microns in diameter. With methenamine silver stain, the PLS were argyrophilic, and thread-like structures were observed in and around them. Most PLS were observed in deep layers of the cortex and subcortical white matter, and were accompanied by small vessels. They were intimately associated with the small-vessel walls and astrocytes. They were composed of two types of fibers. The first type comprised straight and loosely interwoven fibers about 25-30 nm in diameter, while the other type evoked tangles. These structures have not been found in other neurodegenerative diseases, including Alzheimer's disease. In addition, to evaluate hyaline arteriosclerosis in DNTC, we examined sclerotic changes of the medullary arteries and assessed white matter lesions in affected patients. In three of four patients with DNTC, sclerosis of the medullary arteries was significantly more extensive than in age-matched controls. In all four patients, the severity of white matter lesions was graded as moderate or severe in the temporal lobe and as mild or moderate in the frontal lobe. Arteriosclerotic changes and white matter lesions can occur without hypertension and beta amyloid deposits in DNTC.

Amyloid beta-Peptides↗
PubMed1998

Neurofibrillary tangles and Alzheimer's disease.

The neuropathological diagnosis of Alzheimer's disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangles formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurons, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenon. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still little understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully reproduce faithfully all the major cellular lesions of the disease.

Alzheimer Disease↗
PubMed2002

NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC).

Diffuse neurofibrillary tangles with calcification (DNTC) is a rare tangle-predominant dementia, as well as one of the tauopathies lacking Abeta deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type calcification and, histopathologically, numerous neurofibrillary tangles in the limbic system and neocortex. Recently, accumulation of alpha-synuclein (alphaS), the precursor of the non-beta amyloid component (NAC) of Alzheimer's disease, has been shown in diverse neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, multiple system atrophy and parkinsonism-dementia complex of Guam. To clarify whether alphaS accumulates in other neurodegenerative disorders, we investigated eight DNTC brains using immunohistochemistry and demonstrated remarkable alphaS deposition in the neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus (five cases). In the hippocampus, many Lewy neurites were distributed in the stratum oriens and stratum pyramidale in the CA2-3 and the subiculum. Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus and temporal cortex. This investigation reveals that neurons and astrocytes are extensively involved in remarkable alphaS pathology in the DNTC brain, and that the alphaS pathology compounds the cardinal pathological features of tau pathology. These findings suggest that (1) DNTC shares a common pathophysiological background with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy in which abnormal alphaS aggregation is observed, and (2) there is an interaction between alphaS and tau pathology that does not involve amyloid in DNTC.

Adult↗
PubMed1985

Monoclonal antibodies to Alzheimer neurofibrillary tangles. 2. Demonstration of a common antigenic determinant between ANT and neurofibrillary degeneration in progressive supranuclear palsy.

Neurofibrillary degeneration is an argyrophilic intraneuronal lesion found in several unrelated neurologic conditions. The relationship between different types of neurofibrillary tangles is investigated with two monoclonal antibodies raised against Alzheimer neurofibrillary tangles (anti-ANT). Using the peroxidase-antiperoxidase technique, the authors demonstrate that neurofibrillary tangles of progressive supranuclear palsy, containing 15-nm straight filaments, share an antigenic determinant with ANTs. Ultrastructural studies localize the antigenic determinant to filamentous elements in the parakarya. The determinant is not present in normal brain, aluminum-induced experimental tangles in the rabbit, Lewy bodies, Hirano bodies, or axonal filamentous inclusions of amyotrophic lateral sclerosis and giant axonal neuropathy. It is, however, present in ANTs regardless of the pathologic condition in which they are found, including Alzheimer's disease, Down's syndrome, and postencephalitic Parkinson's disease.

Alzheimer Disease↗
PubMedDate not supplied

Modeling the relation between neurofibrillary tangles and intellectual status.

The relationship between the neurofibrillary tangles and the intellectual deficit observed in senile dementia of the Alzheimer type was studied in 27 patients over the age of 75. The presence and density of tau positive tangles were assessed in six areas including limbic, paralimbic, and isocortical cortices. In the isocortical areas, the presence [1] or absence [0] of neurofibrillary tangles was better correlated with the Blessed test score than the density of the neurofibrillary tangles profiles. Multivariate analysis showed that the number of areas containing at least one neurofibrillary tangle was the best explanatory variable of the intellectual status. The cortical areas were ranked according to the prevalence of their involvement. The presence of tangles in an area of a given rank took place only if the areas of lower ranks were also involved. It is proposed that the presence of tangles in a given area is a more significant information than the value of their density. These data may lead to new diagnostic procedures.

Aged↗
PubMed1990

Ultrastructural evidence that insoluble microtubules are components of the neurofibrillary tangle.

The ultrastructure of Alzheimer's neurofibrillary tangles is heterogeneous and includes abnormal paired helical filaments (PHF) and various other insoluble structures. Insoluble non-PHF components isolated from neurofibrillary tangles were examined by electron microscopy. Comparison of these fractions with normal assembled neurofilaments and normal brain microtubules revealed scattered profiles which were morphologically (not chemically) identical to structures present in the microtubule, but not in the neurofilament preparations. These results support the notion that insoluble microtubules contribute to the make up of the neurofibrillary tangle. Based on these findings, preliminary experiments were conducted which suggest that non-enzymatic glycosylation may be a pathway leading to insolubility of the microtubules.

Aged↗
PubMed1998

Argyrophilic structures stimulate glial reactions in neurofibrillary tangles and senile plaques.

Neurofibrillary tangles (NFT) and senile plaques (SP) contain various pathological structures, and the majority of these pathological structures are argyrophilic. To investigate the glial reactions of the argyrophilic substance, we performed immunohistochemistry for microglia or for astroglia after Gallyas-Braak staining, which is one of the most sensitive silver impregnation techniques detecting argyrophilic structures in NFT and SP. We found that extracellular argyrophilic structures in NFT and SP showed glial reactions, and we observed reactive microglia in the center of NFT and SP in contrast to astroglia, which were situated in the periphery. These findings suggest that the exposed argyrophilic components in the extracellular space stimulate both glial reactions, but that there is a striking difference in localization between microglia and astroglia.

Alzheimer Disease↗
PubMed2005

Visualization of newly deposited tau in neurofibrillary tangles and neuropil threads.

Neurofibrillary tangles (NFTs) and neuropil threads (NTs), the major hallmark of Alzheimer disease (AD), are composed of the microtubule-associated protein tau that has undergone posttranslational modifications, including deamidation and isomerization on asparaginyl or aspartyl residues. Because such modifications represent protein aging, we generated 2 antibodies, TM4, specific for Asp-387 of tau, and iD387, specific for isoAsp-387 of tau, to investigate the evolution of NFTs and NTs. On Western blots of Sarkosyl-insoluble fractions, TM4 strongly labeled paired helical filament-tau (PHF-tau), whereas iD387 preferentially labeled PHF smear. Thus, it is reasonable to postulate that TM4-labeled tau (unmodified tau species) represents more recent deposition, and iD387-labeled tau (modified tau species) represents earlier deposition. Unexpectedly, TM4 immunostained even highly evolved NFTs, suggesting that deposition of newly produced tau continues until neuronal death. iD387 labeled the whole profile of NFTs up to distal dendritic branches, whereas TM4 staining was localized to particular portions of NFTs in proximal dendrites and neuronal perikarya. In NTs, TM4 preferentially labeled the outer portion, whereas iD387 intensely labeled the core portion. Based on TM4-positive NFT counts and total NFT counts, we speculate that NFTs in the human hippocampus are produced at a constant rate irrespective of the disease stage.

Alzheimer Disease↗
PubMed2001

Neurofibrillary tangles and tau phosphorylation.

Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with beta-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated alpha-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 beta (GSK-3 beta) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3 beta distribution showing that developmental evolution of GSK-3 beta compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 beta activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing beta-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation.

Alzheimer Disease↗
PubMed1994

Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: a combined in situ hybridization and immunocytochemical investigation.

Neurofibrillary tangle formation, a cardinal characteristic of Alzheimer's disease, is also a feature of several other neurodegenerative disorders, including subacute sclerosing panencephalitis (SSPE). In the present study the association of measles virus genome with neurofibrillary tangle formation has been studied in five cases of SSPE, using in situ hybridization (measles genome) and immunocytochemistry (tau, ubiquitin and beta/A4 amyloid). In two cases with duration of disease less than one year, neurofibrillary tangle formation was not observed. However, in those cases in which the disease was of several years duration, numerous tau- and ubiquitin-positive neurofibrillary tangles were demonstrated. In the two cases of longest duration, double-labelling techniques demonstrated the frequent association of neurofibrillary tangle formation with neuronal measles virus genome positivity. Immunocytochemistry for beta/A4 amyloid failed to demonstrate amyloid in any of the five cases. These findings support the hypothesis that neurofibrillary tangle formation can occur independently of amyloid formation and that this mechanism may operate in both Alzheimer's disease and in virally-induced disease.

Adolescent↗
PubMed1992

Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: a quantitative analysis of six cases.

Progressive supranuclear palsy is characterized neuropathologically by the presence of high densities of neurofibrillary tangles in several subcortical structures. In some cases, neurofibrillary tangles have also been described in the cerebral cortex. We performed a quantitative regional and laminar analysis of the distribution of these lesions in six cases of progressive supranuclear palsy. We observed that the neurofibrillary tangle distribution in the cerebral cortex was largely confined to the hippocampal formation. In particular, in all the cases neurofibrillary tangles were observed in the granule cell layer of the dentate gyrus. In the prefrontal and inferior temporal cortex, neurofibrillary tangles were predominantly distributed in layers II and III. In addition, there were moderate-to-high neurofibrillary tangle densities in the primary motor cortex. This localization pattern contrasts with the neurofibrillary tangle distribution observed in the cerebral cortex of Alzheimer's disease cases, where tangles are denser in layer V than in layer III, and where the primary motor cortex and the dentate gyrus are usually not involved. These results suggest that specific elements of the cortical circuitry might be differentially vulnerable in progressive supranuclear palsy as compared to Alzheimer's disease.

Aged↗