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PubMed1992

Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala.

We report a family in which 13 members in three generations had the presenile (age 42 to 66 years) onset of dementia with an autosomal dominant pattern of inheritance. An early symptom in eight individuals was prominent antisocial psychotic or belligerent behavior, often leading to the initial clinical diagnosis of paranoid schizophrenia. Duration of illness was longer than is usual in Alzheimer's disease (AD), ranging from 14 to 26 years in six members. Three affected siblings and a cousin have come to autopsy, and all had neurofibrillary tangles without senile plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus. The hippocampus was free of both neurofibrillary tangles and senile plaques in all four, but in three there was neuronal loss with gliosis in the CA1 region of Ammon's horn bilaterally. There also was neuronal loss and neurofibrillary tangles in the nucleus basalis. The neurofibrillary tangles were tau-2 and Alz-50 positive and were composed of paired helical filaments ultrastructurally. The disease in this kindred appears to be a unique hereditary disorder that is distinct from familial AD.

Alzheimer Disease↗

PubMed1995

Neurofibrillary tangles in chronic alcoholics.

Magnocellular neurons in the cholinergic nucleus basalis appear to be vulnerable in a variety of pathological conditions, including chronic alcoholism. While neurofibrillary degeneration of these neurons has been noted in a number of disorders characterized by dementia, the mechanism of cell death in thiamine-deficient chronic alcoholics has not been identified. In the present post-mortem investigation, multiple brain regions of seven thiamine-deficient chronic alcoholics, three neurologically asymptomatic chronic alcoholics and seven non-alcoholic age matched controls were screened for neurofibrillary pathology using both tau-immunohistochemistry and a modified Bielschowsky silver stain. In chronic alcoholics with thiamine deficiency, neurofibrillary pathology was found in the nucleus basalis, but not any other brain region. Neurofibrillary tangles were not seen in age-matched controls and were infrequent in alcoholics without neuropathological signs of thiamine-deficiency. Neurofibrillary tangles were most numerous in those cases with cell loss in the nucleus basalis. These findings suggest that neurodegeneration of the nucleus basalis in chronic alcoholics proceeds through the formation of neurofibrillary tangles.

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PubMed1993

Immunocytochemical evidence that the beta-protein precursor is an integral component of neurofibrillary tangles of Alzheimer's disease.

Amyloid beta (A beta) immunoreactivity has been demonstrated in all extracellular neurofibrillary tangles (E-NFT) and most intraneuronal neurofibrillary tangles (I-NFT). We undertook this immunocytochemical study to understand the relationship between A beta immunoreactivity localized in NFT and beta-protein precursor (beta PP). We found epitopes of amino-, mid-, and carboxyl-terminal domains of beta PP in I-NFT and the majority of E-NFT. NFT retained beta PP after ionic detergent extraction, demonstrating that beta PP is an integral component of NFT. Finding beta PP in regions of A beta immunoreactivity raises the possibility that beta PP or its fragments associate with amyloid, and that the stability of A beta is responsible for its dominance in amyloid deposits.

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PubMed1991

Tau in Alzheimer neurofibrillary tangles. N- and C-terminal regions are differentially associated with paired helical filaments and the location of a putative abnormal phosphorylation site.

To investigate the extent to which whole tau proteins, structurally abnormal tau and fragments of tau are incorporated into neurofibrillary tangles in Alzheimer's disease, an immunocytochemical mapping study using a panel of antibodies to several synthetic human tau peptides has been performed. Neurofibrillary tangles were immunolabelled in situ, and paired helical filaments (PHF), the principal structural component of tangles, were immunolabelled after isolation and Pronase treatment. N-Terminal and C-terminal domains of tau were found to be present in tangles in situ. SDS-treated PHF were found to contain most of the C-terminal half of tau and were also labelled by antibodies to ubiquitin. Only some of these PHF were labelled by antisera to tau sequences towards the N-terminus, and this enabled the identification of a region of tau in which proteolytic cleavage may occur. The ultrastructural appearance of the immunolabelling suggested that both the N- and C-terminal domains of tau extend outwards from the axis of PHF. After Pronase treatment. PHF were strongly labelled only by an antiserum to PHF and by the antiserum to the most C-terminal tau synthetic peptide. The latter antiserum also strongly labelled extracellular tangles in situ, whereas these extracellular tangles were poorly labelled by the antisera to the other synthetic peptides. One anti-(tau peptide) serum labelled a population of neurofibrillary tangles in situ only after alkaline phosphatase pretreatment of tissue sections. Our results show that, although peptides along the length of the tau molecule are associated with neurofibrillary tangles in situ, only the C-terminal one-third of the molecule is tightly associated with PHF, since this region of tau is resistant to SDS treatment of PHF. We also report the existence in PHF in situ of a masked tau epitope which is partially unmasked by dephosphorylation. These results are indicative of post-translational changes in tangle-associated tau in degenerating neurons in Alzheimer's disease.

Alzheimer Disease↗

PubMed1993

Quantitative immunohistochemical analysis of the distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of nonagenarians and centenarians.

To investigate the neuropathological differences between normal aging and senile dementia of the Alzheimer type (SDAT) in very old people and to see how they compare with a younger population of demented elderly people, we performed an immunohistochemical quantitative analysis of the topography of senile plaques and neurofibrillary tangles in a series of 31 elderly patients aged from 96 to 102 years. According to the medical records, two groups were considered: 7 patients presenting with clinically documented SDAT and 24 patients with no or very mild cognitive impairment. The densities of senile plaques were comparable in both groups. Extensive neurofibrillary tangle formation was restricted to the CA1 hippocampal field of demented subjects, whereas the superior frontal cortex showed rare neurofibrillary tangles, independently of the clinical diagnosis. These results indicate an absence of direct correlation between the number of senile plaques and the clinical manifestation of SDAT. Furthermore, they suggest that the dementing process may involve different cortical structures in nonagenarians and centenarians than in younger demented individuals where a widespread cortical involvement is generally observed. Thus, the neurofibrillary tangle density in the CA1 field may be critical for the neuropathological diagnosis of SDAT in this particular group of very old patients.

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PubMedDate not supplied

An immunohistochemical study of neurofibrillary tangle formation in post-encephalitic Parkinsonism.

Neurofibrillary tangle (NFT) formation is a feature of postencephalitic Parkinsonism (PEP) and Alzheimer's disease (AD). Tangle formation has been compared immunohistochemically in these 2 conditions. Staining patterns for tau protein, ubiquitin and beta/A4 amyloid protein were studied in frontal lobe, hippocampus, and midbrain in 2 classical cases of PEP, 2 cases of AD and 2 controls matched for age and sex. NFTs were present in all cases, but with varying frequency: all tangles were tau-positive and many were ubiquitinated. In the frontal cortex and hippocampus, irrespective of the case category, tangle formation was associated with beta/A4 amyloid deposition. A similar association was present in the 2 AD cases in the midbrain. However, in PEP tangle formation in the midbrain was not associated with adjacent beta/A4 amyloid deposition. This finding raises the possibility that the pathogenetic mechanism of tangle formation in PEP is different from that of AD, although the final cellular morphological expression of abnormality in both conditions is similar.

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PubMed1994

Rabbit IgG cross-reacts with Alzheimer neurofibrillary tangles.

Biochemical studies have demonstrated that the paired helical filaments (PHF) of Alzheimer neurofibrillary tangles are mostly made up of tau and to a lesser degree of ubiquitin and other proteins. In addition, immunocytochemical labeling of tangles with antibodies to various other neuronal proteins has been shown previously. We report here the labeling of the locations of PHF, i.e., Alzheimer neurofibrillary tangles, neuropil threads and plaque neurites in tissue sections with a goat antiserum to rabbit IgG (GAR-T). The labeling is comparable in strength and distribution to that of tau and ubiquitin antibodies. The PHF-staining antibodies could be removed by absorption with native rabbit IgG but not with human IgG, IgG-depleted rabbit serum, rabbit IgG heavy chains or light chains eluted from nitrocellulose membranes. Furthermore, the PHF reactivity was obliterated by absorption with brain homogenate and a fraction enriched in soluble abnormally phosphorylated tau, but not with purified bovine tau or SDS-washed preparations of the relatively insoluble population of PHF. On immunoblots of both normal human tau and Alzheimer abnormally phosphorylated tau-enriched preparations, GAR-T labeled a set of three to five polypeptides in the tau region. Some of these polypeptides co-migrated with the tau bands. These results indicate (i) that PHF in Alzheimer's disease brain cross-react with a structural epitope/s present on native rabbit IgG, and (ii) that the cross-reactivity with PHF is probably due to tau.

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PubMed1994

Neurofibrillary tangles in the cerebral cortex of sheep.

Neurofibrillary degeneration, including neurofibrillary tangles (NFTs) and neuritic plaques, is an important pathological hallmark of Alzheimer's disease (AD). Unfortunately, no practical animal model of neurofibrillary degeneration has been described. We report here the presence of structures in the cerebral cortex of sheep, Ovis aries, that resemble Alzheimer NFTs and neuritic plaques. NFT-like structures and clusters of degenerating neurites are stained by silver impregnation and thioflavin-S, and are immunoreactive with antibodies against tau microtubule-associated proteins. Viewed under the electron microscope, tau-immunoreactive tangles consist of paired helical filaments. Naturally occurring neurofibrillary structures in sheep cortex provide a model for studying the pathobiology of Alzheimer's disease.

Animals↗

PubMed1979

The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy.

The fine structure of subcortical neurofibrillary tangles was investigated in pallidum, substantia nigra, periaqueductal gray, pontine reticular gray, and dentate nucleus of 5 autopsy cases of Progressive Supranuclear Palsy. Only tangles due to straight 150 A wide filaments have been detected. These findings, obtained from a large series of cases and areas examined, confirm previous observations on the fine structure of neurofibrillary tangles in Progressive Supranuclear Palsy and suggest that the association between tangles due to straight filaments and tangles due to twisted tubules, so far described in one case, is probably exceptional.

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PubMed1996

Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins.

Guamanian parkinsonism-dementia, locally described as bodig, is characterized by the widespread appearance of neurofibrillary tangles in cortical and subcortical areas. These tangles have similar regional distribution and immunohistochemical profile to those found in Alzheimer disease (AD). We studied the immunohistochemical staining of these tangles, as well as those of AD, using antibodies to complement proteins and related molecules. In bodig, as in AD, extracellular tangles were intensely decorated with antibodies to C1q, C4d and C3d, but not fraction Bb of factor B, properidin or immunoglobulins. This is evidence that the classical, but not the alternative complement pathway is activated on extracellular tangles and that the activation is independent of antibodies. Immunohistochemical staining for amyloid P, an in vitro activator of complement, was remarkably similar to that for the C1q, C4d and C3d in both bodig and AD. This was not the case for beta-amyloid protein (BAP), another in vitro complement activator. Positive staining was observed in only a minority of extracellular tangles in bodig and was only rarely observed in those of AD. BAP would therefore not appear to be a candidate for activating complement on extracellular neurofibrillary tangles. Reactive microglia and reactive astrocytes were closely associated with complement positive extracellular neurofibrillary tangles, indicating an inflammatory response similar to that seen in AD.

Adult↗

PubMed1979

Evidence that Alzheimer neurofibrillary tangles originate from neurotubules.

Antiserum against normal human neurotubules purified by in-vitro assembly precipitated both neurotubules and a polypeptide isolated from Alzheimer neurofibrillary tangles in Ouchterlony double-diffusion tests. The antiserum specifically labelled neurofibrillary tangles, in isolated neurons by immunofluorescence and in tissue sections by the peroxidase-antiperoxidase technique. These results indicate that neurofibrillary tangles in Alzheimer's disease probably originate from neurotubules.

Adult↗

PubMed1993

Alzheimer neurofibrillary tangles contain 2.1 nm filaments structurally identical to the microtubule-associated protein tau: a high-resolution transmission electron microscope study of tangles and senile plaque core amyloid.

Alzheimer neurofibrillary tangles (NFT) and senile plaque core amyloid (SPCA) isolated from the brain of patients with Alzheimer's disease were freeze-dried and replicated with a new platinum-carbon (Pt-C) vertical deposition method for high-resolution transmission electron microscopy (TEM). The resolution of this vertical Pt-C replication method is superior to either of the more conventional 20 degrees rotary replication or 45 degrees unidirectional replication methods and is dependent on the Pt-C film thickness coating the specimen. The paired helical filaments (PHF) observed within the tangles were right-handed helices with a fairly regular twist period averaging 79.3 +/- 5.9 nm and a fairly regular maximum width averaging 14.9 +/- 1.0 nm. The PHF regions of minimum width were not regular and fell into three size categories: 2.4 +/- 0.3 nm, 4.9 +/- 0.6 nm and 9.6 +/- 1.4 nm. In addition to the PHF found in the tangles, a new filament was found within all the tangles. These 2.1 +/- 0.2 nm diameter filaments were triple-stranded left helices with 1.0 +/- 0.2 nm diameter strands with a structure identical to bovine tau. Like bovine tau polymer a number of filaments (130 nm to 238 nm) were longer than a fully stretched tau monomer of 96 nm. Images of neuritic senile plaque core amyloid (SPCA) showed that amyloid had a more solid appearance than the NFT and its branched filament structures were unlike the approximately 2.1 nm diameter filaments or the PHF found in NFT.

Alzheimer Disease↗

PubMedDate not supplied

Reduced GAP-43 message levels are associated with increased neurofibrillary tangle density in the frontal association cortex (area 9) in Alzheimer's disease.

We previously suggested the hypothesis that defective neuronal plasticity is a major neurobiological deficit causing the dementia of Alzheimer's disease (AD). We used message levels of the growth-associated protein, GAP-43, as a marker of axonal plasticity to examine the hypothesis of defective neuronal plasticity in AD. When all AD cases are combined, the average level of GAP-43 message in area 9 of the AD frontal association cortex was not significantly different from the level in the comparably aged control cortex. Differentiation of AD cases on the basis of neurofibrillary tangle (NFT) density revealed that in AD cases with high tangle density average GAP-43 message level was reduced fivefold relative to levels in AD cases with low NFT density. AD cases with low neurofibrillary tangle density had levels of GAP-43 message that were not significantly different from the levels of normal controls. Differentiation of AD cases on the basis of neuritic plaque density did not indicate as strong a relationship to GAP-43 message level. The association between neurofibrillary tangle density and GAP-43 message level suggests the hypothesis that neurofibrillary tangles may reduce GAP-43 expression. Data of others show a relationship between high NFT density and reduced levels of synaptophysin-like immunoreactivity and reduced cerebral glucose metabolism. These data combine to suggest a set of AD cases with high NFT density, reduced axonal plasticity, reduced synaptic density, and reduced cerebral glucose metabolism--all variables that may be directly related to the functioning of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1989

Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease.

The intraneuronal accumulation of paired helical filaments in the form of neurofibrillary tangles is one hallmark of the brain pathology in Alzheimer's disease. At certain predilection sites, a small number of similar lesions are also present in the brains of the majority of aged non-demented individuals. As suggested by several studies before, these abnormal cytoskeletal structures contain determinants of microtubule-associated protein tau and ubiquitin. The present study uses a morphological classification of neurofibrillary tangles into different stages of maturation, as suggested by Alzheimer in 1911, and shows by quantitative immunocytochemistry that early stages of neurofibrillary degeneration contain abnormally phosphorylated tau. Immunoreactivity for the altered tau is seen not only in tangles but also in the cytoplasm of some nerve cells lacking neurofibrillary tangles. Similar numbers of such immunoreactive neurons without tangles are present in age-matched non-demented individuals as in Alzheimer cases, but are absent in young controls. In contrast, incorporation of an epitope, recognized by a monoclonal antibody (3-39) raised to paired helical filaments, which is directed against a determinant residing in the 50-65 amino acid residue region of ubiquitin occurs late in the process of tangle maturation and is most pronounced in extracellular 'ghost tangles'. It is suggested that the accumulation of abnormally phosphorylated tau is one of the earliest cytoskeletal changes in the process of tangle formation. Exposure of certain ubiquitin epitopes in the pathological fibers may reflect an unsuccessful attempt of proteolytic degradation.

Adult↗

PubMed1992

Immunohistochemical, ultrastructural and immunoelectron microscopic studies of spinal cord neurofibrillary tangles in progressive supranuclear palsy.

Immunohistochemical, ultrastructural and immunoelectron microscopic studies of spinal cord neurofibrillary tangles (NFTs) in progressive supranuclear palsy (PSP) were performed. The spinal cord NFTs reacted with antibodies to tau protein (tau-2), ubiquitin and Alzheimer neurofibrillary tangles (ANTs, Ab 39). Ultrastructurally, the NFTs consisted of bundles of straight fibrils. In longitudinal sections, the individual NFT fibrils appeared as straight fibrils with a diameter of approximately 15 nm. In cross sections, circular structures approximately 15 nm in diameter were seen, and some had a central density. Electron microscopic examination of specimens stained with the antibodies and by the modified Bielschowsky method revealed the products of the tau, ubiquitin and ANTs immunoreactions and silver deposits on the NFT fibrils. This is the first demonstration of the ultrastructure of spinal cord NFTs in PSP.

Adult↗

PubMed1988

Saccharides of senile plaques and neurofibrillary tangles in Alzheimer's disease.

The contribution that oligosaccharides might make to the structure of the senile plaque and the neurofibrillary tangle was investigated using lectin histochemistry in 9 patients with Alzheimer's disease. One group of 4 lectins diffusely stained the neurites of senile plaques whereas two groups of 6 different lectins stained neurofibrillary tangles within neuronal perikarya and plaque neurites. Neuraminidase pretreatment abolished staining of tangles by one of these latter groups, but did not affect staining by the other group. Senile plaque core amyloid failed to stain with any lectin. It is concluded that oligosaccharides may contribute, but in different ways, to glycoprotein or glycolipid residues that form an integral part of the structure of the senile plaque and the neurofibrillary tangle.

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PubMed1987

Neurofibrillary tangles in association with congenital hydrocephalus.

Morphologic study of the brain from a retarded patient with progressive congenital hydrocephalus revealed widespread neurofibrillary tangles in the cerebral cortex and the brain stem. Senile plaques were not found. The tangles consisted of paired helical filaments. Scanning electron microscopic energy spectrometric analysis failed to demonstrate abnormal accumulation of aluminum or other elements in the involved neurons.For the first time the association of congenital hydrocephalus and neurofibrillary tangles is reported. This observation is consistent with the hypothesis of interference with axonal transport of neurofilaments as a common pathogenetic mechanism in the genesis of neurofibrillary tangles in human brains.

Adult↗

PubMed1981

The relationship between formation of senile plaques and neurofibrillary tangles and changes in nerve cell metabolism in Alzheimer type dementia.

Nerve cell nucleolar volume in reduced, in senile dementia of Alzheimer type, by 15 - 25% in nerve cells not containing neurofibrillary tangles and by over 35% in those which do contain such changes, in a wide variety of brain regions, when compared to similar cells from non-demented control cases, suggesting that interference with production of proteins may be an early consequence of the pathogenic process. The extent to which nucleolar volume is decreased in the non-tangle-bearing cells is related to frequencies of both neurofibrillary tangle and senile-plaque formation within that region, but the reduction in volume in the tangle-bearing cells correlated with neurofibrillary changes only. It seems, therefore, that the severity with which the dementing process affects an area of brain is initially shown by alterations in cell metabolism, which may invoke reductions in protein synthesis in non-tangle-bearing cells, and is later marked by the proportion of these affected cells which go to form neurofibrillary tangles. Changes in nerve cell function do not seem to be as well indicated by the density of senile plaques within that area.

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