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PubMed1989

A4 amyloid protein immunoreactivity is present in Alzheimer's disease neurofibrillary tangles.

Neurofibrillary tangles and neuritic plaques are the neuropathological hallmarks of Alzheimer's disease. The latter consist of a core of A4 amyloid protein. We now report that some neurofibrillary tangles ('tombstone tangles') are also A4 immunoreactive. This observation is consistent with the hypothesis that A4 amyloid accumulation is a component of both neurofibrillary tangles and neuritic plaques.

Alzheimer Disease↗

PubMed1992

What's new in the pathology of neuronal cytoskeleton: the significance of neurofibrillary tangles.

Neurofibrillary tangles are a neuronal change observed in various conditions, linked with dementia when affecting the cerebral cortex as in Alzheimer's disease. They may be found locally close to fibrous or vascular tumors, or affect extensive regions of the neocortex while the cerebellum and the medulla are not affected. Recent immunological and biochemical studies demonstrate that the MT-associated protein tau is the main component of the tangles, in an abnormally phosphorylated state. A consequence of the formation of tangles is a decreased assembly of MT in axons and dendrites, with disturbances of neuroplasmic flow. The relations between tangles and amyloid, as seen in Alzheimer's and Down's diseases are topographical, tangles accumulating in particular in neurites close to the amyloid in the senile plaques (but also at distance in cell bodies and neurites). Genetically and biochemically A4 or beta-amyloid and tau differ. The exact relation between the beta-pleated proteins of tangles and amyloid remain poorly understood.

Amyloid beta-Peptides↗

PubMed1991

The hypothesis of zinc deficiency in the pathogenesis of neurofibrillary tangles.

Neurofibrillary tangles (NFT) in human encephalopathies of various etiologies may result from a common pathogenetic mechanism: a functional zinc decrease leading to a deficiency of the DNA metabolizing zinc-enzymes, giving rise to abnormal neuronal DNA and synthesis of pathological proteins: NFT. In encephalopathia Saturnica, zinc decreases in the hippocampus displaced by lead; in Guam's encephalopathy, calcium deficiency permits the entry in the brain of toxic metals that may displace zinc; in Boxer's dementia and some viral encephalitides, blood-brain-barrier (BBB) is altered and abnormal metals may reach the brain; in Down's syndrome and Alzheimer's disease precapillary and capillary amyloidosis disturbs the BBB, metals (iron and aluminium) are encrusted in the amyloid and their brain level increases, whereas zinc decreases especially in the hippocampus. A deficiency of the zinc enzymes of neuronal detoxication, of glutamate catabolism and of some neurotransmitters metabolisms may also contribute in the neuronal dysfunction of these encephalopathies. A non-toxic zinc compound crossing the BBB may be useful for the treatment of these encephalopathies and especially for Alzheimer's disease.

Alzheimer Disease↗

PubMed1991

Ultrastructural localization of beta-amyloid, tau, and ubiquitin epitopes in extracellular neurofibrillary tangles.

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer disease, are commonly located in perikarya of neurons. In advanced cases of Alzheimer disease, however, NFTs are observed also in the extracellular space. As extracellular NFTs (E-NFTs), and occasionally intracellular NFTs (I-NFTs), are recognized by antibodies to beta-amyloid protein (beta AP), beta AP may be present not only in amyloid deposits but also in paired helical filaments (PHFs), the primary components of NFTs. We compared the antigenic characteristics of I-NFTs and E-NFTs with light- and electron-microscopic immunocytochemistry by using several antibodies to noncontiguous epitopes of the microtubule-associated protein tau and of ubiquitin (Ub) as well as an antiserum to beta AP. At variance with I-NFTs, E-NFTs were made predominantly of straight filaments (SFs), rather than PHFs, that were often separated by astroglial processes and in close association with small beta AP deposits. Occasionally, E-NFTs were made of bundles of amorphous material, which showed no resemblance to SFs, PHFs, or amyloid fibrils. The antigenic changes in E-NFTs suggest that when NFTs become extracellular they lose the N and, possibly, the C termini of tau while maintaining the intermediate region of the molecule; they also lose the N-terminal two-thirds of Ub while the C-terminal conjugation site of Ub is preserved. A small subset of E-NFTs reacted with antibodies to both beta AP and tau. Although in most E-NFTs, the epitopes recognized by tau and Ub antibodies were located in typical PHFs and SFs, the epitopes recognized in this subset of anti-beta AP and anti-tau-positive E-NFTs were located exclusively in the bundles of amorphous material. It is suggested that either beta AP epitopes are present but inaccessible in PHFs and SFs and become exposed after conformational changes occurring in the extracellular space or PHFs and SFs become closely associated with beta AP in the extracellular space.

Alzheimer Disease↗

PubMed1990

Relative abundance of tau and neurofilament epitopes in hippocampal neurofibrillary tangles.

Neurofibrillary tangles (NFTs) derive, in part, from normal neuronal cytoskeletal proteins, ie, large portions of tau (tau) but only restricted segments of the peripheral domains of the high- and middle-molecular weight neurofilament subunits. To learn more about the events leading to the incorporation of tau and neurofilament epitopes into NFTs, the relative abundance of tau and NF determinants in these lesions was quantitatively analyzed in hippocampi from Alzheimer disease (AD) patients and age-matched controls using monoclonal antibodies specific for tau or for NF proteins. Immunostained NFTs appeared qualitatively the same in both AD and controls, ie, every epitope found in AD NFTs occurred also in the NFTs of the control patients. However, in hippocampi with only a few tangles, tau epitopes, but no NF epitopes, were detected in NFTs. In contrast, both tau and NF epitopes were present in those tangles that were found in hippocampi with abundant NFTs. Nevertheless, the number of tau-positive NFTs generally exceeded the number of NF-positive NFTs. These findings indicate that tau epitopes are more abundant than NF epitopes in NFTs and that the formation of NFTs may be linked to a derangement in the normal metabolism of tau that is more extensive than alterations in NF protein metabolism.

Antibodies, Monoclonal↗

PubMed1992

Evidence that neurofibrillary tangles undergo glial modification.

Ghost tangles, neurofibrillary tangles (NFTs) emerging into extracellular space, appear to be subjected to some microglial association in addition to an invasion of astrocytic processes. Our findings lead us to speculate that the NFTs undergo structural and immunocytochemical modification. Electron microscopic observation of the NFTs in the vascular region indicated either the discharge of NFTs into the vessel or formation of NFTs in the astrocytic end-foot.

Aged↗

PubMed1991

Basic fibroblast growth factor binding is a marker for extracellular neurofibrillary tangles in Alzheimer disease.

Neurofibrillary tangles (NFT) are abnormal filamentous inclusions that develop in neurons in Alzheimer disease and other disorders. When neurons die, the neurofibrillary tangles that persist in the extracellular space show ultrastructural and antigenic changes. Both intra- and extracellular NFT have recently been shown to contain heparan sulfate proteoglycans (HSPGs). HSPGs are also present in other amyloid deposits in the brain and in systemic amyloidoses. Basic fibroblast growth factor (bFGF) is a heparin binding growth factor which is involved in angiogenesis and also has neurite promoting activity. We now report that bFGF binds avidly to extracellular NFT. Alz-50, a monoclonal antibody (MAb) to an abnormal form of tau and bFGF binding label mutually exclusive subpopulations of neurofibrillary tangles. bFGF binding is abolished by heparinase or heparitinase treatment and therefore is most likely based on the presence of HSPG. Binding of bFGF is a specific and sensitive morphological method to distinguish intra- from extracellular NFT. As intracellular NFT, which also contain HSPGs, are not labeled by bFGF binding, this finding also suggests that HSPGs are modified when the NFT become extracellular.

Aged↗

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↗

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↗

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↗

PubMed1987

Ganglioside monoclonal antibody (A2B5) labels Alzheimer's neurofibrillary tangles.

Ganglioside monoclonal antibody (A2B5) labels Alzheimer's neurofibrillary tangles both in isolated neurofibrillary tangle-bearing nerve cells and in partially purified preparations of tangle fibers. Antibody staining was preabsorbed by preincubation of antibody with neuronal ganglioside preparations. These results suggest that Alzheimer's neurofibrillary tangles have a ganglioside associated with them.

Alzheimer Disease↗

PubMed1988

Distribution of precursor amyloid-beta-protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques.

Neurofibrillary tangles (NFT) and neuritic plaques (NP), two neuropathological markers of Alzheimer disease, may both contain peptide fragments derived from the human amyloid beta protein. However, the nature of the relationship between NFT and NP and the source of the amyloid beta proteins found in each have remained unclear. We used in situ hybridization techniques to map the anatomical distribution of precursor amyloid-beta-protein mRNA in the neocortex of brains from three subjects with no known neurologic disease and from five patients with Alzheimer disease. In brains from control subjects, positively hybridizing neurons were present in cortical regions and layers that contain a high density of neuropathological markers in Alzheimer disease, as well as in those loci that contain NP but few NFT. Quantitative analyses of in situ hybridization patterns within layers III and V of the superior frontal cortex revealed that the presence of high numbers of NFT in Alzheimer-diseased brains was associated with a decrease in the number of positively hybridizing neurons compared to controls and Alzheimer-diseased brains with few NFT. In contrast, no correlation was found between the densities of NP and neurons containing precursor amyloid-beta-protein mRNA transcripts. These findings suggest that the expression of precursor amyloid-beta-protein mRNA may be a necessary but is clearly not a sufficient prerequisite for NFT formation. In addition, these results may indicate that the amyloid beta protein, present in NP in a given region or layer of cortex, is not derived from the resident neuronal cell bodies that express the mRNA for the precursor protein.

Aged↗

PubMed1991

Glutamate-, glutaminase-, and taurine-immunoreactive neurons develop neurofibrillary tangles in Alzheimer's disease.

Although formation of neurofibrillary tangles is a major pathological feature of Alzheimer's disease (AD), the neurotransmitter content of neurofibrillary tangle-bearing neurons has not been well characterized. We studied the hippocampus of 6 patients with pathologically verified AD and 6 control subjects using a monoclonal antibody to glutamyl-glutamate and polyclonal antisera against glutaminase and taurine. In normal hippocampus, glutamate and glutaminase stained pyramidal neurons in the cornu ammonis (CA) fields and the subiculum, as well as the dentate granule cells. Fiber staining was better seen with glutamate antisera, which in AD specimens showed reduced numbers of glutamate-immunoreactive fibers in the molecular layer of the dentate gyrus. In AD specimens, glutamate- and glutaminase-immunoreactive pyramidal neurons in the hippocampal CA fields were decreased in number and remaining neurons showed irregular shortened and disorganized dendritic fields. Taurine immunoreactivity was localized to a subset of hippocampal pyramidal neurons, which showed similar degenerative changes in AD specimens. Glutamate-, glutaminase-, and taurine-stained neurons were found to contain neurofibrillary tangles using either double immunofluorescence with tau antisera, double immunoperoxidase stains, or silver and thioflavine S counterstains. These studies show that two distinct neurochemically defined populations of pyramidal neurons in allocortex frequently show degenerative changes and develop neurofibrillary tangles in AD.

Aged↗

PubMed1975

Distribution of Alzheimer's neurofibrillary tangles in the basal ganglia and brain stem of progressive supranuclear palsy and Alzheimer's disease.

The authors studied the distribution of neurofibrillary tangles in the basal ganglia and brain stem of progressive supranuclear palsy and Alzheimer's disease, with the result that almost no similarity in the distribution and frequency of neurofibrillary tangles exists between both diseases. In two cases with progressive supranuclear palsy, neurofibrillary tangles were found most numerously in the subthalamic nucleus. Next in order came the globus pallidus, reticular formation of midbrain, pons and medulla oblongata, pontine nuclei, locus coeruleus, red nucleus, substantia nigra, periaqueductal grey matter and olivary nuclei. Neurofibrillary tangles were rare in the thalamus. In two cases with Alzheimer's disease, neurofibrillary tangles were found most numerously in the nucleus mamilloinfundibularis, nucleus basilaris, nucleus dorsalis raphe, nucleus centralis superior, and next in order came the thalamus. They were found scarcely in the lenticular nuclei and reticular formation of the pons. In both diseases, almost no neurofibrillary tangles were found in the nucleus supraopticus, nucleus paraventricularis, nuclei tuberales and nuclei corporis mamillare.

Aged↗

PubMed1988

Antigenic characteristics of neurofibrillary tangles in progressive supranuclear palsy.

The antigenic components of neurofibrillary tangles in the basal forebrain and brainstem were studied in 4 cases of progressive supranuclear palsy (PSP) at the light and electron microscopic levels, using antibodies to neurofilaments (in the phosphorylated and non-phosphorylated forms); the high, middle and low molecular weight neurofilament subunits; ubiquitin; the microtubule associated proteins MAP1, MAP2 and tau; isolated Alzheimer paired helical filaments and to tubulin, in the tyrosinated and detyrosinated forms. Although PSP neurofibrillary tangles appear to have most antigenic sites in common with those of Alzheimer disease, PSP tangles share epitopes with tyrosinated and detyrosinated tubulin, which has not been demonstrated in Alzheimer neurofibrillary tangles.

Aged↗

PubMed1991

Neurofibrillary tangle distribution in the cerebral cortex of parkinsonism-dementia cases from Guam: differences with Alzheimer's disease.

Parkinsonism-dementia together with amyotrophic lateral sclerosis is a highly prevalent disorder among the native Chamorro population of Guam and is accompanied by severe widespread neurofibrillary tangle formation. In the present study we compared the regional and laminar distribution of neurofibrillary tangles in the cerebral cortex of 5 Guamanian parkinsonism-dementia cases to 9 Caucasian Alzheimer's disease cases. Although in both diseases the superior frontal and inferior temporal cortex were affected to a comparable degree, there was a striking difference in the laminar distribution of neurofibrillary tangles. Neurofibrillary tangles in Alzheimer's disease are known to be more numerous in layers V-VI than in layers II-III of frontal and temporal cortex, however in the Guam cases, the opposite distribution was observed with most of the tangles located within layer II and the superior part of layer III and relatively low tangle density in layers V-VI. Interestingly, in both conditions, the hippocampal pyramidal layer showed a comparable degree of degeneration. Moreover no amyloid deposits and neuritic plaques were observed in the Guam brains, whereas they were frequent in the Alzheimer's disease cases. Previous studies have suggested that the clinical symptomatology observed in patients suffering from Alzheimer's disease is related to the dramatic loss of specific corticocortically projecting neurons in the neocortex. The present data on Guam parkinsonism-dementia further support this hypothesis, although the set of corticocortical connections affected in Guam cases might differ from that observed in Alzheimer's disease, which may contribute to some extent to the different clinical symptoms of the dementia observed in Guamanian patients.

Aged↗

PubMed1987

Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders.

Neurofibrillary tangles occur in a number of apparently distinct neurodegenerative diseases and in normal aging of the human brain. Antibodies raised against Alzheimer's disease paired helical filaments immunolabel the tangles seen in all other tangle-associated disorders examined to date. The neuronal microtubule-associated protein, tau, has recently been identified as an antigenic component of neurofibrillary tangles and senile plaque neurites in Alzheimer's disease. Three different polyclonal antibodies with strong tau immunoreactivity are examined in this study. These antibodies were found to immunostain tangles in normal aged brain and in brains affected by a range of neurodegenerative disorders, including Down's syndrome, Alzheimer's disease plus Parkinson's disease, progressive supranuclear palsy, and the parkinsonism-dementia complex of Guam, as well as Pick bodies in Pick's disease. The findings further illustrate the relative nonspecificity of neurofibrillary lesions in neurodegenerative disorders.

Aged↗

PubMed1992

Distribution of neurofibrillary tangles and senile plaques in the cerebral cortex in postencephalitic parkinsonism.

Postencephalitic parkinsonism is characterized neuropathologically by severe loss of pigmented neurons in the substantia nigra and the presence of high densities of neurofibrillary tangles in several brainstem structures. In 5 cases of postencephalitic parkinsonism, we observed that the neurofibrillary tangle distribution in the cerebral cortex predominated in the hippocampus and entorhinal cortex. In the prefrontal and inferior temporal cortex, neurofibrillary tangles were preferentially localized in layers II and III. This pattern contrasts with the neurofibrillary tangle distribution observed in neocortical areas of Alzheimer's disease cases, where neurofibrillary tangles are denser in layer V than in layer III. These results suggest that specific elements of the cortical circuitry might be differentially affected in postencephalitic parkinsonism as compared to Alzheimer's disease, and that cortical involvement is likely to be a common feature of this condition.

Aged↗