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PubMed2006

Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy.

Myotonic dystrophy (MyD) is a neuromuscular degenerative disorder that is neuropathologically characterized by minor changes, such as the presence of neurofibrillary tangles (NFT), thalamic inclusions and functional brainstem lesions. In the current study, we conducted an immunohistochemical analysis to examine the distribution of NFT and formation of oxidative products in the brain specimens of 12 patients with MyD. Neurofibrillary tangles were found in the limbic system and/or the brainstem of all the cases examined but there were no senile plaques. The density of distribution of the NFT was not significantly correlated with clinicopathological findings, although cases with fewer NFTin the brain frequently showed sleep disturbances and lack of spontaneity. Nuclear and cytoplasmic immunoreactivities for 8-hydroxy-2'-deoxyguanosine and advanced glycation end products were observed in the glial cells and/or neurons in the brainstem, but not in the cerebral cortex. On the other hand, 10 out of the 12 cases showed cytoplasmic immunoreactivity for 4-hydroxy-2-nonenal-modified protein (4-HNE) in neurons of the temporal cortex and raphe nucleus. Deposition of 4-HNE was also recognized in the hippocampus and mesencephalic central gray matter, but not in the subiculum. The distribution pattern of the immunoreactivity for 4-HNE showed no clear correlation with either the psychological disturbances or the distribution of the NFT. Altered expression of monoaminergic neurons in the brainstem of MyD patients has already been reported, and it is worth noting that most of our cases showed NFT in the brainstem. The selective deposition of 4-HNE in the limbic system and brainstem suggests that lipid peroxidation may be involved in the neurodegenerative process in MyD. Using immunohistochemical analysis to determine the distribution of neurotransmitters in the mesencephalic central gray matter and/or pontine raphe nucleus may help elucidate the relationship between the clinical abnormalities, distribuion of NFT, and 4-HNE deposition in the brain in patients with MyD.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

Direct determination of the proportion of intra- and extra-cellular neocortical neurofibrillary tangles in Alzheimer's disease.

We investigated the cellular localisation of neurofibrillary tangles in Alzheimer's disease. All tau-positive tangles were stained for thioflavine S, while approximately 84% of thioflavine S-stained tangles were tau-immunolabelled. Approximately 58-62% and 73-76% of thioflavine S- and tau-labelled tangles, respectively, were present within cortical neurons labelled for microtubule-associated protein-2. Thus, most neocortical tangles in Alzheimer's disease are intracellular and may not be the principal cause of neocortical cell loss.

Aged↗

PubMed1989

Along the way to a neurofibrillary tangle: a look at the structure of tau.

We report our ongoing work to characterize the molecular nature of neurofibrillary tangles (NFT). An epitope map of tau protein using monoclonal antibodies that crossreact with NFT reveals the presence of epitopes that span the entire tau molecule from the amino terminus to the carboxy terminus. Several antibodies that recognize tau protein including Alz50 do not recognize primary amino acid sequence but are directed either against a post-translational modification or a complex higher order structure. The importance of tau protein in the development of the pathology is underscored by the extent of the tau-reactive neuritic lesions. These dystrophic neurites or "curly fibers" extend well beyond the classical distributions of the senile plaques and NFT. Furthermore, the neuropil lesion is considerably more extensive than either the senile plaques or neurofibrillary tangles. One of the features of the dystrophy in Alzheimer's disease is widespread neuronal sprouting characteristic of dystrophic neurites and tangle-bearing cells.

Alzheimer Disease↗

PubMed1994

Familial Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles.

Patients affected with Gerstmann-Sträussler-Scheinker disease from two families, one from Indiana and one of Swedish origin, have been studied. The patients are clinically characterized by cerebellar ataxia, extrapyramidal signs, and dementia. Accumulation of amyloid deposits and neurofibrillary tangles are the most conspicuous neuropathologic features. In the patients from the Indiana family, the amyloid contains an 11-kDa peptide, an amyloidogenic degradation product of the prion protein. The neurofibrillary tangles are composed of paired helical filaments and immunoreact with antibody to A68, an abnormally phosphorylated form of the microtubule-associated protein tau. In these families, the disease is caused by a point mutation in the PRNP gene. In the Indiana family, the mutation is at codon 198, and in the Swedish family at codon 217.

Aged↗

PubMed1997

Tau in aluminum-induced neurofibrillary tangles.

Aluminum is a neurotoxin and in susceptible species induces a neurofibrillary pathology characterized by argentophilic masses in neuronal perikarya and in axonal spheroids. These inclusions are known to contain neurofilament proteins. Using immunocytochemistry and immunoblotting, we demonstrate that tau is a component of these aluminum-induced neurofibrillary tangles (Al-NFTs) in rabbits. Double-label immunocytochemistry experiments reveal co-localization of phosphorylated neurofilaments (using SMI31) and tau (using tau-1, tau-5, AT8, and PHF-1) in the perikaryal Al-NFTs. Non-phosphorylated tau (detected using tau-1) occupies a smaller area of the Al-NFT than the total pool of tau proteins (detected using tau-5). The area of total tau and non-phosphorylated tau immunolabeling in the Al-NFT increases as the size of the Al-NFT (i.e., the proportion of cell area occupied by the Al-NFT) increases. The proportion of cell area (outside of the Al-NFT) occupied by tau (as indicated by tau-5) decreases as the area of tau in the Al-NFT increases and as the size of the Al-NFT in the cell increases. Immunoblotting experiments demonstrate 1) the specificity of the tau antibody labeling and verify a lack of cross-reactivity of the tau-5 antibody to neurofilament proteins in rabbit tissue; and 2) no alterations in the levels of tau resulting from aluminum-treatment. These data suggest that as the size of the Al-NFT in a cell increases there is less tau in the neuronal perikarya. Therefore, there may be less tau in the perikarya available to perform normal functions such as microtubule polymerization and stabilization. Tau and neurofilament proteins are perturbed in a number of neurodegenerative disorders such as Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease. Aluminum-induced neurofibrillary pathology may provide a model to study perturbation in tau and neurofilaments, their phosphorylation and deposition into pathological inclusions.

Aluminum↗

PubMed1994

A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads.

Frontal sections of the temporal lobe including the transentorhinal/entorhinal region, amygdala, and/or hippocampus from human adult brains are studied for cytoskeleton changes using immunostaining with the antibodies AT8 and Alz-50 and selective silver impregnation methods for neurofibrillary changes of the Alzheimer type. For the purpose of correlation, the two methods are carried out one after the other on the same section. Layer pre-alpha in the transentorhinal/entorhinal region harbours nerve cells which are among the first nerve cells in the entire brain to show the development of neurofibrillary changes. This presents the opportunity for study of both early events in the destruction of the cytoskeleton in individual neurons, and to relate changes which occur in the neuronal processes in the absence of alterations in their immediate surroundings to those happening in the soma. Immunoreactions with the AT8 antibody in particular reveal a clear sequence of changes in the neuronal cytoskeleton. Group 1 neurons present initial cytoskeleton changes in that the soma, dendrites, and axon are completely marked by granular AT8 immunoreactive material. These neurons appear quite normal and turn out to be devoid of argyrophilic material when observed in silver-stained sections. Group 2 neurons show changes in the cellular processes. The terminal tuft of the apical dendrite is replaced by tortuous varicose fibres and coarse granules. The distal portions of the dendrites are curved and show appendages and thickened portions. Intensely homogeneously immunostained rod-like inclusions are encountered in these thickened portions and in the soma. A number of these rod-like inclusions are visible after silver staining, as well. Group 3 neurons display even more pronounced alterations of their distal--most dendritic portions. The intermediate dendritic parts lose immunoreactivity, but the soma is homogeneously immunostained. Silver staining reveals in most of the distal dendritic parts neuropil threads, and in the soma a classic neurofibrillary tangle. Group 4 structures are marked by accumulations of coarse AT8-immunoreactive granules. Silver staining provides evidence that the fibrillary material has become an extraneuronal, "early" ghost tangle. Finally, group 5 structures present "late" ghost tangles in silver-stained sections but fail to demonstrate AT8 immunoreactivity. It is suggested that the altered tau protein shown by the antibody AT8 represents an early cytoskeleton change which eventually leads to the formation of argyrophilic neurofibrillary tangles and neuropil threads.

Adult↗

PubMedDate not supplied

Use of bomb pulse carbon-14 to age senile plaques and neurofibrillary tangles in Alzheimer's disease.

The time course of formation of neurofibrillary tangles (NFT) and senile plaques (SP) in Alzheimer's disease (AD) brain is unknown. Above ground nuclear weapons testing in the late 1950s and early 1960s led to significantly increased levels of 14C in the atmosphere and carbon cycle. Because the amyloid beta peptide of SP and paired helical filaments of NFT, once formed, are relatively resistant to degradation, 14C levels observed in SP and NFT should reflect their year of formation. The purpose of this study was to develop a method to determine whether 14C levels could be used to define NFT and SP ages. Using accelerator mass spectrometry to measure bomb-pulse 14C levels, we determined the average age of formation of isolated SP and NFT fractions in bulk brain samples of 6 AD subjects. Although preliminary, the results demonstrate that it is possible to use bomb pulse 14C to determine the average year of formation of NFT and SP in the brain in AD. In addition, the data show that these structures, once formed, have a much slower carbon turnover rate than normal brain and are not in a formation/enzymatic degradation equilibrium.

Aged↗

PubMed1992

Casein kinase II is associated with neurofibrillary tangles but is not an intrinsic component of paired helical filaments.

Neurofibrillary tangles (NFT) are pathological cytoskeletal structures composed of paired helical filaments (PHF), and are found in neurons of patients afflicted with many neurodegenerative disorders, including Alzheimer's disease (AD). We previously found that an antiserum against casein kinase II (CK-II) stained NFT intensely in the brain tissue of AD patients. In the current study, we found that the anti-CK-II antiserum stains NFT and neuronal inclusions in many other neurodegenerative diseases as well, including Guam-Parkinson dementia complex, chromosome 18 deletion syndrome, progressive supranuclear palsy, Kufs' disease, and Pick's disease. This antiserum reacted, in crude brain homogenates, with both a doublet of Mr 43,000 and a Mr 27,000 Da protein which could correspond to the alpha, alpha', and beta chains of CK-II. The staining of these bands was adsorbed by preincubating anti-CK-II antiserum with purified CK-II. Preincubation of brain sections with purified CK-II strongly intensified the immunostaining of NFT with anti-CK-II, suggesting that NFT may bind CK-II. In the AD brain homogenates, the particulate CK-II levels are increased whereas the cytosolic levels are decreased without a change in total CK-II levels, consistent with the idea that CK-II binds to the particulate PHF, a major constituent of NFT. In accord with these findings, purified PHF bound CK-II, but purified PHF did not contain CK-II as its component. These results suggest that CK-II might be an extraneously deposited component of NFT. Thus, the altered CK-II compartmentalization might have significant consequences in the pathogenesis of AD.

Brain↗

PubMed2003

Alpha-synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification.

alpha-Synuclein is known to be a major constituent of the Lewy bodies (LBs) in Parkinson's disease (PD) and the neuronal and glial cytoplasmic inclusions (NCIs, GCIs) in multiple system atrophy. alpha-Synuclein-positive inclusions such as LBs, NCIs and GCIs sometimes show colocalization with tau-positive neurofilaments. Studies using alpha-synuclein immunohistochemistry have often found LBs in the amygdala of patients with familial or sporadic Alzheimer's disease (AD), as well as in patients with Down's syndrome and AD. However, no studies have reported alpha-synuclein-positive structures in cases of diffuse neurofibrillary tangles with calcification (DNTC), which is characterized by numerous neurofibrillary tangles (NFTs) throughout the cerebral cortex but few, if any, senile plaques. We investigated the distribution of alpha-synuclein-positive structures in two cases of DNTC: a 65-year-old woman (brain weight, 850 g) and a 75-year-old woman (brain weight, 800 g). In both cases, severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, alpha-synuclein-positive intracytoplasmic inclusions and neurites were found in the superior temporal lobe (within the temporal pole), amygdala, parahippocampus, entorhinal cortex and insula, the regions most affected by the NFTs. alpha-Synuclein-positive intracytoplasmic inclusions were rare or absent in other regions of the cerebral cortex and brainstem. This distribution pattern differs from that of PD or dementia with LBs. Our findings suggest that the accumulation pattern of alpha-synuclein is a pathological feature of DNTC, and that DNTC is associated with accumulation of both tau and alpha-synuclein.

Aged↗

PubMed1986

Electron microscopic localization of Alzheimer neurofibrillary tangle components recognized by an antiserum to paired helical filaments.

Paired helical filaments (PHF) are the main component of the Alzheimer neurofibrillary tangle; however, other elements, such as 10 and 15 nm straight filaments and granular amorphous components, are observed. In the present study, the localization of the antigenic determinants recognized by an antiserum to PHF fractions that does not recognize normal nervous tissue components is examined by electron microscopic immunocytochemistry. Employing the peroxidase-antiperoxidase procedure on neurofibrillary tangles in intact tissue, we found that the antiserum reacts with PHF and with granular amorphous material within the tangle. Following isolation of PHF by treatment with ionic detergent and labeling with immunogold, the antigenic determinants often occur at intervals rather than being uniformly distributed along the PHF. The distribution of the antigenic determinants recognized by this antiserum is similar to that previously observed for PHF determinants recognized by antibodies to neurofilament and microtubule-associated proteins. We conclude that PHF are heterogenous structures which contain PHF-specific as well as cytoskeleton-derived antigenic determinants.

Aged↗

PubMed1996

Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease.

Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.

Alzheimer Disease↗

PubMed1991

Multicatalytic proteinase is present in Lewy bodies and neurofibrillary tangles in diffuse Lewy body disease brains.

A non-lysosomal multicatalytic proteinase (MCP) is immunohistochemically visualized in Lewy bodies and loosely arranged globose tangles but not in the majority of compact neurofibrillary tangles in brains with cortical diffuse Lewy body disease. Virtually all Lewy bodies are immunoreactive to MCP, exhibiting various staining patterns where they are moderately diffuse, intense in the central core or intense in the peripheral rim. MCP may be involved in the formation of these inclusions.

Aged↗

PubMed1997

Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism-dementia complex of Guam.

We found tangle-associated neuritic clusters (TANCs), previously reported as being present in Alzheimer's disease (AD), to be common in early and mild cases of the parkinsonism-dementia complex of Guam (PDC, bodig disease). These entities were observed around extracellular neurofibrillary tangles (eNFTs), apparently as a transient phenomenon. They were not observed around normal neurons, or neurons with intracellular neurofibrillary tangles (iNFTs). They were also not observed around late stage eNFTs. The TANCs contained both type 1 (elongated) and type 2 (globular) dystrophic neurites, as well as small, granular structures. The type 1 dystrophic neurites in TANCs were immunostained by antibodies to neuroskeletal proteins, while type 2 dystrophic neurites were immunostained by antibodies to amyloid precursor protein (APP). The eNFTs surrounded by TANCs were almost all immunopositive for amyloid P, while only some were immunopositive for C4d, and only a minority had beta-amyloid protein (A beta) associated with them. We hypothesize that the eNFTs are a source of complement activation which results in destruction of surrounding neurites. We further hypothesize that the degenerating neurites are a source of A beta which forms long-term deposits around eNFTs.

Aged↗

PubMedDate not supplied

Neurons bearing neurofibrillary tangles are responsible for selected synaptic deficits in Alzheimer's disease.

The observation that neurons containing neurofibrillary tangles are usually adjacent to neurons free of any morphological indication of disease, suggests the hypothesis that it is NFT-bearing neurons that are primarily responsible for the loss of function in AD. Quantitative Golgi postmortem studies from our laboratories have indicated that there is in many regions of the brains of nondemented humans an age-related increase in dendritic extent of single neurons. In Alzheimer's disease, this normal, age-related increase in dendritic extent was not found, leading to the hypothesis that one of the neurobiological defects in AD is a failure of neuronal plasticity. Message levels of the growth-associated protein, GAP-43, in frontal association cortex (area 9/46) indicated that AD brains with the highest density of neurofibrillary tangle-bearing neurons, showed GAP-43 message levels decreased of the order of 6-fold relative to AD brains with the lowest density of NFT. Combined immunocytochemistry to differentiate tangle-bearing from tangle-free neurons with in situ hybridization to define relative GAP-43 message levels in single neurons revealed that grain density over tangle-bearing neurons containing nuclei was reduced 3-fold compared to that over adjacent tangle-free neurons. This reduction in expression of GAP-43 message in tangle-bearing neurons was selective, because using probes for other messages showed that grain density over tangle-bearing neurons was, on average, increased or similar to that over adjacent non-tangle-bearing neurons. Message levels for the synaptic vesicle-associated protein, synaptophysin, have also been found to be reduced in tangle-bearing neurons relative to adjacent tangle-free neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2003

[An autopsy case of argyrophilic grain dementia with abundant neurofibrillary tangles].

We reported an autopsy case of "senile dementia" showing neuropathologically abundant neurofibrillary tangles(NFT) and argyrophilic grains(AG) without senile plaques. A Japanese woman developed memory disturbance when she was 70 years old. The patient was hospitalized at age 80 and a cranial CT scan revealed bilateral mild atrophy of the temporal lobes and mild enlargement of the lateral ventricle, especially in the inferior horn. She died at the age of 80. Autopsy showed that her brain weighted 1220 g. Numerous NFT were found in the entorhinal (trans-entorhinal) region, subiculm, CA1-CA4, dentate gyrus, amygdala, nucleus basalis of Meynert, substantia nigra, and locus coeruleus. Furthermore, numerous AG were seen in the temporal lobe(T3, T4), amygdala, prominently in the basolateral nuclei. Obvious neuronal loss with gliosis was noted in the temporal lobes, including the hipocampal regions. Few senile plaques was detected in temporal lobe(T4). Sarkosyl-insoluble tau extracted from the temporal lobe consisted predominantly of four-repeat tau isoforms. To our knowledge, this is the first report of argyrophilic grain dementia complicated with tangle only dementia.

Aged↗

PubMed1989

Ultrastructure of neurofibrillary tangles in Alzheimer's disease.

The ultrastructure of neurofibrillary tangles (NFT) was examined by electron microscopy. The fibrils of NFT seemed to consists of about eight protofilaments consisting of globular subunits; these protofilaments were helically wound in a longitudinal direction. The fibrils of NFT had hollow structures at their centers surrounded by the eight globular subunits. The subunits were tightly connected in the narrow parts of the fibril, but more loosely connected in the wider parts. From these findings, it seemed that the fibrils of NFT consist of a twisted tubule having periodical constrictions and is made up of eight helically wound protofilaments, forming globular subunits.

Alzheimer Disease↗

PubMed2002

Neurofibrillary tangles in the primary motor cortex in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. The cortical pathology of the disease is characterized by the widespread occurrence of cortical neurofibrillary tangles that exhibit a specific laminar and regional distribution different from that seen in Alzheimer's disease (AD). In spite of the major motor symptomatology, the degree to which the primary motor cortex is affected in this disease has not been investigated in detail. We report here that the primary motor cortex in Guamanian cases contains high numbers of neurofibrillary tangles, contrasting sharply with the situation in AD and in non-Chamorro cases of amyotrophic lateral sclerosis. Furthermore, the cases with predominant parkinsonism-dementia are more severely affected than amyotrophic lateral sclerosis cases. These data suggest that the regional and cellular pathology of Guamanian cases differs radically from that commonly observed in neurodegenerative diseases outside Guam and point to the existence of subgroups in the spectrum of clinical manifestations seen in Guamanian patients.

Aged↗

PubMed1994

A quick silver method for senile plaques and neurofibrillary tangles in paraffin sections.

A new silver method for senile plaques and neurofibrillary tangles (NFT) in paraffin sections is presented. This new technique is rapid in execution (15 min) and reveals senile plaques of all morphological types as well as NFT. The silver staining is spatially congruent with immunocytochemical staining for the beta-amyloid peptide (A beta) in adjacent sections.

Alzheimer Disease↗