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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↗
PubMed1980

Immunohistochemical characterization of neurofibrillary tangles induced by mitotic spindle inhibitors.

Neurofibrillary tangles were induced in the motor neurons of the rabbit spinal cord by the intrathecal injection of colchicine, vinblastine, and vincristine. The tangles stained intensely by immunofluorescence and by the peroxidase-anti-peroxidase procedure using neurofilament antisera raised against chicken brain antigen, as previously reported for aluminum-induced neurofibrillary tangles. No immunohistochemical reactivity could be demonstrated between the tangles and a 150,000 dalton bovine neurofilament antiserum, although the adjacent axons were intensely stained in cryostat sections of the spinal cord.

Animals↗
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↗
PubMed1984

Alzheimer neurofibrillary tangles: monoclonal antibodies to inherent antigen(s).

Using isolated Alzheimer neurofibrillary tangles as the immunogen, nine mouse hybridomas were generated which produced antibodies to the tangles as tested in both tissue sections and isolated neurons from Alzheimer brain. Extraction of isolated neurofibrillary tangles with 2% SDS could not remove the antigen(s) with which these monoclonal antibodies reacted. Immunocytochemical study revealed that each of the monoclonal antibodies reacted with one or more of other tissue antigens in addition to the Alzheimer tangles. However, no reaction with either neurofilaments or microtubules was observed with any one of these antibodies. This is the first demonstration of monoclonal antibodies which have been generated against isolated Alzheimer neurofibrillary tangles; these antibodies react with antigen(s) inherent to the tangles.

Alzheimer Disease↗
PubMed2003

Cdk5: one of the links between senile plaques and neurofibrillary tangles?

The relationship between amyloid plaques and neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's disease (AD), is an unknown and controversial subject. However, emerging evidence from genetic and biochemical studies suggests that accumulation of amyloid beta peptides may play a causative role in AD pathogenesis. This led to the amyloid hypothesis, which proposes that amyloid beta peptides disrupt neuronal metabolic and ionic homeostasis and cause aberrant activation of kinases and/or inhibition of phosphatases. The resulting alteration in kinase and phosphatase activities ultimately leads to hyperphosphorylation of tau and formation of neurofibrillary tangles. Cyclin-dependent kinase 5 (Cdk5) is a tau kinase whose activity is induced by amyloid beta peptides. Its deregulation may represent one of the signal transduction pathways that connect amyloid beta toxicity to tau hyperphosphorylation. This article reviews the functions and regulation of Cdk5. Evidence that suggests deregulation of Cdk5 activity in AD by virtue of calpain cleavage of its activator p35 to p25 will be discussed.

Alzheimer Disease↗
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↗
PubMed1994

Amyotrophic lateral sclerosis and parkinsonism-dementia from Guam: differences in neurofibrillary tangle distribution and density in the hippocampal formation and neocortex.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex is a highly prevalent neurodegenerative disorder among the native Chamorro population of Guam, and is characterized by widespread formation of neurofibrillary tangles. In the present study, the distribution of neurofibrillary tangles was quantitatively assessed in the cerebral cortex of cases presenting with either predominant amyotrophic lateral sclerosis or parkinsonism-dementia symptomatology. Results show that although the regional and laminar lesion distribution is qualitatively similar in both groups, cases with predominant parkinsonism-dementia generally have higher lesion densities than cases with amyotrophic lateral sclerosis. Interestingly, layer II of the entorhinal cortex was affected to the same degree in both conditions. In both groups, the CA1 field of the hippocampus, subiculum, and entorhinal cortex were the most affected areas. In the neocortex, the perirhinal and inferior temporal cortex consistently had higher lesion densities than the frontal, parietal, and cingulate cortex, whereas the visual cortex was practically devoid of lesions. Also, most of the neurofibrillary tangles were located in the supragranular layers of the neocortex, with relatively low densities in the infragranular layers, in both brain groups. Interestingly, the primary motor cortex contained more neurofibrillary tangles in parkinsonism-dementia than in amyotrophic lateral sclerosis cases. It is possible that the differences in regional neurofibrillary tangle densities reflect the variable severity of the dementing process observed between the two groups of patients. Several studies on Alzheimer's disease and related disorders indicate that the regional and laminar cortical localization of neurofibrillary tangles may parallel the degeneration of specific corticocortical projections. The present data suggest that the population of corticocortical projections involved in Guamanian cases differs substantially from that affected in Alzheimer's disease. The differential distribution and densities of the lesions may contribute to the differences in symptomatology and severity of dementia among Alzheimer's disease and Guamanian cases, although these neurodegenerative disorders as well as related illnesses may share certain etiopathogenetic mechanisms.

Adult↗
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↗
PubMed2005

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease.

Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.

Aged, 80 and over↗
PubMed1997

Scanning electron microscopical study of the neurofibrillary tangles of Alzheimer's disease.

Neurofibrillary tangles (NFTs) have been ultrastructurally studied by various methods, leading to several three-dimensional models of paired helical filaments (PHFs). In this study, we present the scanning electron microscopic findings of NFTs in an autopsy case of Alzheimer's disease and clarify the three-dimensional structures of NFTs. NFTs were clearly defined in freeze-cracked nerve cells and consisted of two types of filamentous structures, straight and helical filaments. Straight filaments measured from 20 to 25 nm in diameter and had a smooth surface. They were slightly bent but mostly straight with no constrictions. One type of straight filaments ran in a bundle in the same direction, another was intertwined to each other. Most of the helical profiles of filaments usually measured about 28 nm in diameter, with a distance of 100 nm between periodic constrictions. They seemed to consist of a pair of isodiametric filaments of 10 nm in diameter. In addition, two unusual types of helical filaments were occasionally observed. One comprised thick filaments of about 38 nm in diameter, with a distance of 100 nm between constrictions; these helical filaments appeared to consist of two or more strands. The other comprised thin helical filaments of about 20 nm in diameter and regularly constricted at an interval of 50 nm. All types of the helical filaments examined in this case were leotropic. This result supports a protofilament model of PHFs. Scanning electron microscopy using the freeze-cracked and maceration method is a useful and simple method for three-dimensional observation of the filamentous structures in NFTs.

Alzheimer Disease↗
PubMed1993

Alzheimer neuropathology in mentally retarded adults: statistical independence of regional amyloid plaque and neurofibrillary tangle densities.

The densities of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed quantitatively in the brains of 303 mentally retarded adults 23 to 90 years of age at the time of their deaths (mean = 59.5 years). Cases with Down's syndrome, hydrocephalus and metabolic disorders were excluded from the study. Examinations of frontal, temporal, parietal, and occipital cortex, as well as hippocampus and parahippocampal gyrus were made in every case. NPs and/or NFTs were observed within the brains of 163 cases (53.8%). Detailed analyses indicated that NP density within all brain regions examined was positively related to age, with the largest age associated increases in density seen in frontal and temporal regions. In contrast, NFT density increased with age only within hippocampus and parahippocampal gyrus, but not neocortex. In addition, NP lesions within neocortex were more diffusely distributed across regions for older compared to younger cases, while no similar age-associated change in the topography of NFTs was observed. Finally, factor analyses of the combined NP and NFT data indicated that, while strong correlations existed across the various brain regions for measures of NP and NFT densities, considered separately, there was virtually no indication of regional associations between these two types of lesions. While these data, from cases with mental retardation, cannot be generalized directly to the nonretarded population, they provide strong evidence that models of Alzheimer pathogenesis must take into account the fact that regional densities of NPs and NFTs, and, therefore, the underlying processes associated with formation of these lesions, can be largely independent.

Adult↗
PubMed1994

Human striatum: the distribution of neurofibrillary tangles in Alzheimer's disease.

The distribution of neurofibrillary tangles and senile plaques was surveyed in the striatum of Alzheimer's disease cases. Neurofibrillary tangles were present throughout the striatum, but displayed significantly higher densities in the nucleus accumbens, olfactory tubercle and tail of the caudate nucleus. Senile plaques with dense amyloid cores showed a similar pattern of distribution. By contrast, non-cored senile plaques were homogeneously distributed in all striatal territories. No tangles and few plaques were observed in the striatum of control cases. These findings suggest that the 'limbic' striatum is preferentially vulnerable to pathology in Alzheimer's disease.

Adult↗
PubMed1999

Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation.

The amyloid cascade hypothesis of Alzheimer's disease postulates that accumulation of amyloid beta-protein (Abeta) precedes neurofibrillary tangle formation or neuronal loss in the cortex. Although this temporal profile has been proved in the neocortex by silver staining and immunocytochemical methods, CA1 of the hippocampus exhibits a distinct temporal profile during normal aging: the formation of neurofibrillary tangles precedes senile plaque formation. This temporal profile has been further confirmed by two-site enzyme immunoassay (EIA) quantitation of sodium dodecyl sulfate (SDS)-dissociable Abeta42; neurofibrillary tangles are already present despite undetectable levels of SDS-dissociable Abeta42. However, when the same specimens were subjected to Western blotting, many cases with or without neurofibrillary tangles showed some accumulation of SDS-stable Abeta dimers that cannot be detected by EIA. Thus, the temporal profile prerequisite for the hypothesis is still valid in CA1, and this finding also suggests that SDS-stable Abeta dimers have some significant effects on CA1 pyramidal neurons, which are most vulnerable to neurofibrillary tangle formation.

Adult↗
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↗
PubMed1995

Numerous glial fibrillary tangles in oligodendroglia in cases of subacute sclerosing panencephalitis with neurofibrillary tangles.

Both neurons and oligodendroglia are preferentially infected in subacute sclerosing panencephalitis (SSPE). Massive argyrophilic and tau-positive glial fibrillary tangles (GFT) were found in oligodendroglia in two autopsy cases of SSPE with neurofibrillary tangles (NFT). GFT shared common phosphorylated tau-epitopes with NFT, but were negative for ubiquitin. Electron microscopically, GFT consisted of compact bundles of irregularly woven tubules. Thus, GFT in SSPE differed from NFT showing regular constriction of tubules and from GFT in some other cytoskeletal disorders in which GFT reportedly consisted of straight tubules.

Adolescent↗
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↗