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PubMed1999

Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: implications for MAP kinase activation in Alzheimer disease.

Indirect evidence suggests that activation of the mitogen activated protein kinase (MAPK) cascade contributes to the hyperphosphorylation of tau found in paired helical filaments in Alzheimer disease (AD). We report colocalization of the activated form of MAPK with Ser 199/202 and Ser 396/404 phosphotau immunoreactive neurofibrillary tangles and neuritic plaques in the Alzheimer brain. Fluorescence resonance energy transfer studies (FRET) demonstrate a tight intermolecular association of activated MAPK with these phosphotau epitopes. These data support the hypothesis that activation of MAPK contributes directly to phosphorylation of tau in AD. Moreover, the stable nature of this association in postmortem human brain may suggest a stable interaction in which activated MAPK becomes tightly linked to neurofibrillary tangles.

Aged↗

PubMed1997

Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus.

Microglial cells are the main component of the brain's resident immune system and are activated in Alzheimer disease (AD). We quantified the density of activated microglial cells (AMG) in 8 sectors of human hippocampus to determine if their density is correlated with senile plaque (SP) and neurofibrillary tangle (NFT) formation. Ferritin-stained microglia, Bielschowsky-stained neuritic plaques, and perikarya containing NFTs were counted in 8 young adults, 9 nondemented elderly adults, and 9 demented patients with AD. Microglial cell activation was moderately higher in elderly nondemented subjects. In AD there was a more striking activation in all sectors of the hippocampus. Most AMGs were distributed diffusely in neuropil and were not delimited to SPs or NFTs. Senile plaque counts were not linked with AMG counts within any sector. Neurofibrillary tangle counts were correlated significantly with AMG counts within one sector, the subiculum. When variations within and between sectors were factored out statistically, the burden of AMGs was correlated significantly with the burden of NFTs (r = 0.34; p < 0.005), but not SPs. Neuropathologic changes at the origin of the perforant pathway were correlated significantly with orthograde microglial cell activation in the termination field. These observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant. When significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.

Adult↗

PubMed1991

Demonstration of neurofibrillary tangles in parvalbumin-immunoreactive interneurones in the cerebral cortex of Alzheimer-type dementia brain.

The pathological changes occurring in a population of parvalbumin-like immunoreactive cerebral cortical interneurones in postmortem Alzheimer-type dementia brain tissue were determined by double staining cerebral cortical sections for parvalbumin, tau and/or calpain-like immunoreactivities. By counting the number of double immunostained cells it was determined that 4% parvalbumin and 25% of calpain-like immunoreactive cells showed evidence of tau-like immunoreactivity, indicative of neurofibrillary tangles. These results suggest that cerebral cortical parvalbumin-like immunoreactive neurones are relatively resistant to the pathological changes underlying the formation of neurofibrillary tangles associated with Alzheimer-type dementia.

Alzheimer Disease↗

PubMed1989

Immunocytochemical profile of neurofibrillary tangles in Down's syndrome patients of different ages.

Brains were obtained at autopsy from 24 patients with Down's syndrome, ranging in age from 13 to 71 years. Neurofibrillary tangle containing neurones of the hippocampus were stained using a Palmgren silver method and immunocytochemically (PAP) using antisera to paired helical filament protein, human tau protein and ubiquitin, as primary antibody. Counts of cells stained by each method were compared. In patients under 50 years of age, in whom only a limited number of tangle bearing cells were present, the number of profiles visualized with silver, anti-paired helical filament and anti-tau methods were similar. However, in patients over 50 years of age (and in certain of those under 50), in whom numerous tangles were present, the number of cell profiles visualized with silver and anti-paired helical filament methods were still similar though anti-tau detected fewer positive cells. This was because of the increased presence, in such patients, of extracellular tangles which had "lost" anti-tau immunoreactivity. Such data suggest that although tau protein forms a major antigenic determinant of neurofibrillary tangles in Down's syndrome (as it does in Alzheimer's disease) this protein may only decorate the basic paired helical filament protein skeleton, and is removed by macrophagic activity upon neuronal death. In all patients, anti-ubiquitin revealed fewer tangles than any other method. It is possible that ubiquitin may be present only transiently, within tangles perhaps following initial formation and lasting only as long as the normal protein degradation processes remain viable within the diseased neurone.

Adolescent↗

PubMed1991

Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein.

Alzheimer's disease (AD) affects more than 30% of people over 80 years of age. The aetiology and pathogenesis of this progressive dementia is poorly understood, but symptomatic disease is associated histopathologically with amyloid plaques, neurofibrillary tangles and neuronal loss primarily in the temporal lobe and neocortex of the brain. The core of the extracellular plaque is a derivative of the amyloid precursor protein (APP), referred to as beta/A4, and contains the amino-acid residues 29-42 that are normally embedded in the membrane-spanning region of the precursor. The cellular source of APP and the relationship of its deposition to the neuropathology of AD is unknown. To investigate the relationship between APP overexpression and amyloidogenesis, we have developed a vector to drive expression specifically in neurons of a C-terminal fragment of APP that contains the beta/A4 region, and have used a transgenic mouse system to insert and express this construct. We report here that overexpression of this APP transgene in neurons is sufficient to produce extracellular dense-core amyloid plaques, neurofibrillary tangles and neuronal degeneration similar to that in the AD brain.

Alzheimer Disease↗

PubMed1998

Identification of septins in neurofibrillary tangles in Alzheimer's disease.

Septins are evolutionarily conserved cytoskeletal GTPases that can form heteropolymer complexes involved in cytokinesis and other cellular processes. We detected expression of the human septin genes Nedd5, H5, Diff6, and hCDC100 in postmortem brain tissues using the reverse transcription-coupled polymerase chain reaction and their products by immunoblot analysis. Four antibodies directed against three septins, Nedd5, H5, and Diff6, consistently labeled neurofibrillary tangles, neuropil threads, and dystrophic neurites in the senile plaques in brains affected by Alzheimer's disease but did not label obvious structures in young control brains. Immunoelectron microscopy revealed that Nedd5 localized to the paired helical filaments. Pre-tangles, the precursory granular deposits that accumulate in the neuronal cytoplasm, also were labeled with the antibodies. These findings suggest that at least the three septins are associated with tau-based paired helical filament core, and may contribute to the formation of neurofibrillary tangle as integral constituents of paired helical filaments.

Adult↗

PubMed1978

Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study.

Topographic analysis was performed of the distribution of Alzheimer's neurofibrillary tangles and the granulovacuolar degeneration of Simchowicz in the hippocampal cortex of patients with Alzheimer's dementia and mentally normal aged controls. A semiautomated scanning stage microscope was linked potentiometrically to an XY pen recorder in order to plot cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of both lesions per cubic mm of pyramidal cortex was quantified by measuring the area of each of six "zones", using a digitizer and programmable calculator. In elderly normal brains as well as those of Alzheimer's disease, the statistically most representative ranking order of predilection for neurofibrillary tangles (in decreasing severity) was: entorhinal cortex greater than subiculum greater than H1 greater than end-plate greater than presubiculum greater than H2. For granulovacuolar degeneration the best rank order was: subiculum greater than H1 greater than H2 greater than end-plate greater than entorhinal cortex greater than presubiculum. The notable similarities of both such orders of predilection to the well-recognized "selective vulnerability" of certain hippocampal neurones in clinical conditions of hypoxia, ischemia and epilepsy suggest some common, focally accentuated cytotoxic mechanism may underlie all these regional predispositions.

Age Factors↗

PubMed1991

Silver staining of senile plaques and neurofibrillary tangles in paraffin sections. A simple and effective method.

A one-step silver staining method using a protective colloidal developer of gelatin and formic acid was originally established for demonstration of argyrophilic nucleolus organizer regions by controlled reduction of silver. We describe here a new application of this silver technique that can easily be performed to demonstrate senile plaques (SP) and neurofibrillary tangles (NFT) on paraffin sections. Preliminary results in ten cases of senile dementia of Alzheimer type and five cases of amyloid congophilic angiopathy showed a reliable demonstration of amyloid and neuritic type SP as well as NFT in all 15 cases. In addition, deposits of perivascular amyloid and areas of fibrillar amyloid, the diffuse type of senile plaques, were revealed. The success seems to depend particularly on the low concentration of formic acid in the developer, which might be the responsible agent for the careful revealing of buried argyrophilic structures in SP and NFT. The staining features were quite similar to those with anti-beta and anti-tau immunostaining. This result suggests a high specificity of this method for extracellular and intraneuronal cerebral amyloid. The detailed staining of delicate morphological structures points to a high sensitivity for cerebral amyloids, senile plaques and neurofibrillary tangles, respectively, by this simple and inexpensive method.

Aged↗

PubMed1985

Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels.

The protein component of Alzheimer's disease amyloid [neurofibrillary tangles (NFT), amyloid plaque core and congophilic angiopathy] is an aggregated polypeptide with a subunit mass of 4 kd (the A4 monomer). Based on the degree of N-terminal heterogeneity, the amyloid is first deposited in the neuron, and later in the extracellular space. Using antisera raised against synthetic peptides, we show that the N terminus of A4 (residues 1-11) contains an epitope for neurofibrillary tangles, and the inner region of the molecule (residues 11-23) contains an epitope for plaque cores and vascular amyloid. The non-protein component of the amyloid (aluminum silicate) may form the basis for the deposition or amplification (possible self-replication) of the aggregated amyloid protein. The amyloid of Alzheimer's disease is similar in subunit size, composition but not sequence to the scrapie-associated fibril and its constituent polypeptides. The sequence and composition of NFT are not homologous to those of any of the known components of normal neurofilaments.

Alzheimer Disease↗

PubMed2000

In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals.

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.

3,3'-Diaminobenzidine↗

PubMedDate not supplied

Subcortical neurofibrillary tangles, neuropil threads, and argentophilic glial inclusions in corticobasal degeneration.

This report concerns an autopsy case of corticobasal degeneration (CBD). The patient was a 64-year-old woman with slowly progressing clumsiness and gait disturbance who died approximately 7 years after the onset of symptoms. The salient neuropathological findings were focal loss of neurons of the cerebral cortex, ballooned neurons and gliosis of the subcortical white matter, thalamus, and basal ganglia. In addition, there were marked neuronal loss and gliosis in the substantia nigra. The ballooned neurons were positively immunostained for phosphorylated neurofilament, alpha B-crystallin and synaptophysin; staining for the latter was intraneuronal. The examination of silver impregnated and Tau immunostained preparations revealed numerous basal neurofibrillary tangles, neuropil threads, and glial inclusions; their presence was most pronounced in the brainstem tegmentum, basal ganglia, and thalamus. Neurofibrillary tangles consisting of straight tubules with a diameter of approximately 13-15 nm and constricted tubules were identified in the substantia nigra. The results of the present study indicate that the cytopathology of the subcortical gray matter and brainstem in CBD patients resembles that of progressive supranuclear palsy.

Axons↗

PubMed1999

Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.

BACKGROUND: The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. DESIGN AND MAIN OUTCOME MEASURES: We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved. CONCLUSIONS: Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

Aged↗

PubMed1991

Ultrastructure of neurofibrillary tangles in Alzheimer's disease by means of tilt-stage electron microscopy.

Neurofibrillary tangles (NFT) in the brains of patients with Alzheimer's disease were examined by means of tilt-stage electron microscopy. Observing a longitudinal direction, constricted parts of the NFT did not move in an axial direction. In a transverse section, a fibril of the NFT consisted of globular subunits having a hollow structure in the center and did not appear as paired filaments. From these findings, it was considered that a fibril of NFT consists of twisted protofilaments made up of globular subunits and does not consist of paired helical filaments.

Aged↗

PubMed2000

Untangling Alzheimer's disease from fibrous lesions of neurofibrillary tangles and senile plaques.

Neuropathological evidence suggests that the two fibril lesions of neurofibrillary tangles (NFT) and senile plaques are the major findings in brain tissue of Alzheimer's disease (AD) and that their occurrence is strongly associated with the symptoms of dementia. Genetic findings have indicated that the pathological molecules from the lesions function as causal agents. There is little evidence, however, to directly indicate that fibril lesions themselves kill neuronal cells in vivo. In spite of such limitations it is important to consider the molecular events involved in AD etiology. In this review of the contribution of Japanese neuropathologists to studies of AD, I will introduce briefly their work and highlight some current topics for consideration on the etiology of AD, and the basis of cell death, and will offer my perspective on outstanding conflicting issues.

Alzheimer Disease↗

PubMed2000

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

Amino Acid Substitution↗

PubMed1992

Beta protein immunoreactivity is found in the majority of neurofibrillary tangles of Alzheimer's disease.

The presence of dystrophic neurites in most extracellular neurofibrillary tangles (E-NFT) suggests a factor promoting neurite growth in E-NFT. Although the beta-protein detected in E-NFT may fill that role, reports that only 2-10% of E-NFT contain beta-protein whereas 80-100% contain dystrophic neurites suggested that beta-protein does not play an important role. In this study, the authors used two antisera and one monoclonal antibody to beta-protein to establish the effects of tissue preparation and formic acid enhancement on the detection of beta-protein in E-NFT. We found that beta-protein epitopes in E-NFT are sensitive to formaldehyde fixation and are best enhanced by 50% formic acid, whereas beta-protein in senile plaques is best enhanced at higher formic acid concentrations. After treatment with 50% formic acid, beta-protein was found in all E-NFT. Interestingly, after treatment with 10% formic acid, half of intraneuronal-NFT (I-NFT) also contained beta-protein immunoreactivity. The finding that beta-protein immunoreactivity in senile plaques, E-NFT and I-NFT is increased at different formic acid concentrations suggests that beta-protein in each location is in a different conformation. In contrast, no beta-protein immunoreactivity could be found in E-NFT of the brain stem, an area in which dystrophic neurites do not infiltrate E-NFT. These findings indicate a correlation between neuritic infiltration and presence of beta-protein in E-NFT and suggests the two are linked in Alzheimer's disease for E-NFT as well as senile plaques.

Aged↗

PubMed1999

[Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies].

We reported a new type of familial Parkinson's disease (familial PD) previously. After that, we examined this family by both the immunohistochemical staining using anti-alpha-synuclein antibody and the analysis of alpha-synuclein gene. We reported these results, and briefly reviewed both familial PD and "familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)". Immunohistochemical staining with anti-alpha-synuclein antibody revealed that the argyrophilic neuronal inclusions and atypical barely tau-positive neurofibrillary tangles were strongly immunoreactive, whereas the ballooned neurons and astrocytic fibrillary tangles were unreactive. DNA analysis of the leukocytes obtained from one live patient of our family did not show any mutations in the entire exons of alpha-synuclein gene. Our results indicated that our family had familial diffuse Lewy body disease with atypical features and without alpha-synuclein gene abnormalities. Features of familial PD included 1) autosomal dominant inheritance, 2) not uncommon atypical clinical features, 3) variable symptomatology and dopa-responsiveness, and 4) low incidence of alpha-synuclein gene abnormalities. Our familial PD showed similar features, and neuropathological findings of our patients also resembled FTPD-17 in the presence of frequent ballooned neurons and neurofibrillary tangles in the cerebral cortex, but were different in the presence of Lewy bodies and paucity of tau pathology.

Humans↗

PubMed1991

Neurofibrillary tangles in dementia pugilistica are ubiquitinated.

Ubiquitin, a protein thought to be involved in the ATP-dependent non-lysosomal degradation of abnormal proteins, has already been identified as a component of neurofibrillary tangles in Alzheimer's disease. We have examined ubiquitin immunoreactivity in a unique collection of brains from 16 ex-boxers including 11 with dementia pugilistica. Neurofibrillary tangles of dementia pugilistica were labelled with an affinity purified antiserum to ubiquitin, and BF10, a monoclonal antibody to a neurofilament epitope.

Adult↗