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PubMed1991

Entorhinal neurofibrillary tangles in Alzheimer disease with Lewy bodies.

Entorhinal cortex is the major source of hippocampal afferents. Its neurons, especially in layer 2, develop neurofibrillary tangles (NFTs) in Alzheimer disease (AD). We quantified entorhinal NFTs in cases of AD, elderly controls, and in brains with both AD pathology and subcortical and neocortical Lewy bodies, (a Lewy body variant, LBV). A nosologic controversy hinges on whether LBVs are a form of AD or a different disease, since they have few neocortical NFTs and their neuritic plaques often lack paired helical filament immunoreactivity. The LBVs had more entorhinal NFTs than controls (P less than 0.001), but fewer than ADs (P less than 0.02), despite comparable numbers of neuritic plaques. AD pathology in LBVs is of moderate severity, or perhaps in an earlier developmental stage.

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PubMed2002

Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections.

An improved thioflavin-S stain, Gallyas silver stain, and two immunostainings were quantitatively compared for demonstration of neurofibrillary tangles (NFTs) on the same sections. Sections of hippocampal formation from seven cases of Alzheimer's disease (AD) were immunofluorescently stained with a commercially available polyclonal NFT antibody or a PHF-1 monoclonal antibody, followed by an improved thioflavin-S stain, and finally by Gallyas silver staining. The thioflavin-S method was improved by using a combination quenching method that removes background autofluorescence without remarkable tissue damage and by post-treatment with concentrated phosphate buffer, which minimizes photobleaching. PHF-1 or NFT immunostaining is much less sensitive than the improved thioflavin-S staining and Gallyas silver staining, particularly in the transentorhinal region. Moreover PHF-1 immunoreactivity varied greatly among AD individuals. Thioflavin-S staining and Gallyas silver staining show almost the same sensitivity in NFT demonstration, but only the former depends on the secondary protein structure of NFTs. This study suggests that the improved thioflavin-S staining is a simple, sensitive, and consistent method for demonstration of neurofibrillary pathology.

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PubMed1999

Frequent coexistence of Lewy bodies and neurofibrillary tangles in the same neurons of patients with diffuse Lewy body disease.

We examined the frequency of neurons with coexistent Lewy bodies (LB) and neurofibrillary tangles (NFT) in diffuse Lewy body disease brains, by a double-immunostaining method using MDV2 and Human tau. Double-positive neurons were frequently observed in the limbic areas. These neurons mostly revealed the feature of intermingled MDV2- and Human tau-positive substances. Immunoelectron microscopically, the MDV2-positive components were not in continuity with the MDV2-negative paired helical filaments (PHF). The MDV2-positive LB were surrounded by the small PHF bundles, frequently accompanied by the randomly oriented PHF within LB. In the intermingled neurons, MDV2-positive non-filamentous components without LB were found among the large PHF bundles. These non-filamentous components may represent the early stage of LB formation.

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PubMed2005

Distribution of cerebral cortical lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of four autopsy cases showing prominent parietal lobe involvement.

We investigated clinicopathologically four Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), which has been believed to be characterized by temporal or temporofrontal circumscribed lobar atrophy, and examined the distribution of their cerebral cortical lesions using hemisphere specimens. The lesions were classified into three categories (slight, moderate, and severe). Severe lesions were present in the temporal lobes and insular gyri of all four cases, consistent with the studies reported to date. In contrast, severe lesions were encountered in the parietal lobe of case 1 and moderate lesions were found in the parietal lobes of cases 2-4. Furthermore, moderate lesions of the precentral gyrus were present in cases 2-4, and moderate lesions of the postcentral gyrus were encountered in all four cases. We postulate that the distribution of cerebral cortical lesions in DNTC is more widespread than previously assumed. Our data also indicate that the unusual clinical signs of DNTC reported by several Japanese researchers, including parietal signs such as apraxia and agnosia, are roughly consistent with the topographic distribution of cerebral cortical lesions in DNTC elucidated in this study.

Brain Diseases↗

PubMed1992

Ultrastructural identification of neurofibrillary tangles in the spinal cords in Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam.

The immunohistochemical and ultrastructural characteristics of spinal cord neurofibrillary tangles (NFTs) were examined in Guamanian amyotrophic lateral sclerosis and in parkinisonism-dementia complex on Guam. The spinal cord NFTs reacted with antibodies to tau protein (tau-2), ubiquitin and paired helical filaments (PHFs). Ultrastructurally, the components of the NFTs were seen as randomly arranged fibrils which were often associated with osmiophilic granules; small bundle-like arrangements were also occasionally observed. Individual NFT fibrils appeared as straight fibrils with a diameter of approximately 15 nm and constricted fibrils with a periodicity of approximately 80 nm. Ultrastructural microscopic examination of specimens stained by the modified Bielschowsky method and with the antibodies revealed silver particles and the products of the tau, ubiquitin and PHF immunoreactions on the NFT fibrils. This is the first demonstration of the fine structure of the spinal cord NFTs.

Adult↗

PubMed2005

Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease.

OBJECTIVE: The present study was performed to compare the distributions of three-repeat (3R) and four-repeat (4R) neurofibrillary tangles (NFT) with those of pretangles (p-NFT), intracellular NFT (i-NFT), and extracellular NFT (e-NFT) in the hippocampus of Alzheimer's disease brains. METHODS: NFT labeling was performed using anti-tau antibodies: pSer262 for p-NFT, pSer422 for i-NFT, AT8 for e-NFT, RD3 for 3R, and RD4 for 4R tau, and Gallyas impregnation for the NFT population. RD4- and pSer422-positive NFT were detected predominantly in sectors from CA2 to CA4, while RD3- and pSer262-positive NFT were predominantly present in CA1, the entorhinal cortex, and the subiculum. The tau epitope recognized by pSer262 belongs to 4R tau but it showed a strong correlation with RD3- and AT8-positive NFT. CONCLUSIONS: Sectors CA2-CA4 showed predominantly 4R-NFT containing the pSer422 epitope. pSer262 may detect the process of transformation from p-NFT to i-NFT, and e-NFT consisted predominantly of 3R tau.

Adult↗

PubMedDate not supplied

KP-1 is a marker for extraneuronal neurofibrillary tangles and senile plaques in Alzheimer diseased brains.

KP-1 immunostaining with microwave pretreatment in formalin-fixed, paraffin-embedded sections enhanced its immunoreactivity revealing extraneuronal neurofibrillary tangles (NFTs) called ghost tangles, senile plaques (SPs) and perivascular deposits as well as microglial labelling in Alzheimer-diseased brains. KP-1 stained cored and uncored SPs, granules within the SPs, perivascular beta-amyloid protein (beta AP) and star-like beta AP deposits in cortical layer I, which was confirmed in comparison to silver-impregnated structures in the Reusche-stained or Gallyas-Schiff-stained sections. On double immunostaining with KP-1 and ubiquitin, ghost tangles were labelled by KP-1 and intraneuronal NFTs were positive for ubiquitin. A few KP-1-positive granules deposits different from amyloid core were found within the SPs and the outer margin of amyloid cores of SPs were stained by KP-1. KP-1-positive microglia were attached to the ubiquitin-positive intraneuronal NFTs. Microglia were more numerously labelled by CR3/43 than by KP-1, and CR3/43-positive microglia were found to be preferentially attached to SPs. As KP-1 recognizes lysosome-associated antigen CD68, similarities between KP-1 positivity and Reusche-stained structures suggested that lysosomal activity was associated with beta AP deposits and ghost tangles were involved in lysosome-associated processes. It is speculated that lysosomes play a role in the process of ghost tangle formation and in beta AP deposits leading to SP formation.

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PubMed2002

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: comparison with late-onset Alzheimer's disease brains.

We quantitatively investigated the formation process of neurofibrillary tangles (NFT) in the hippocampus of 32 brains from non-demented elderly persons using tau-immunohistochemistry, compared with 13 brains from patients with late-onset Alzheimer's disease (AD). The 32 non-demented elderly brains were classified into 16 brains in group I and 16 brains in group II mainly based on the distribution of tau-positive neurons in the hippocampus. Tau-positive neurons were found predominantly in the CA2 in group I, while they were found predominantly in the subiculum-pre-CA1 in group II. Most late-onset AD brains showed a distribution of tau-positive neurons similar to that in group II. In addition, the distribution pattern of tau-positive neurons in the hippocampus was closely related to degeneration of the perforant pathway with the accumulation of tau. These findings suggest that NFT occur first in the CA2 and extend to the subiculum-pre-CA1 in group I, while they occur first in the subiculum-pre-CA1 and extend to the CA2 later in group II, and that the NFT occurring in the subiculum-pre-CA1 are mainly related to degeneration of the perforating route and in the CA2 are related to the degeneration of the non-perforating route.

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PubMed1992

Apolipoprotein B immunoreactivity in senile plaque and vascular amyloids and neurofibrillary tangles in the brains of patients with Alzheimer's disease.

Based upon our previous finding of the association of apolipoprotein E (apoE) immunoreactivity with cerebral amyloids and neurofibrillary tangles (NFTs), we examined immunohistochemically whether this is also the case for apolipoprotein B (apoB). Polyclonal antibody to apoB immunosustained senile plaque amyloid, vascular amyloid, subpial amyloid deposits and intracellular NFTs in formalin-fixed, paraffin-embedded brain sections from patients with Alzheimer disease. Hydrated autoclave pretreatment of the sections enhanced the staining of plaque amyloid. The results may suggest a role of apoB in amyloid and NFT formation.

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PubMed1987

Neurofibrillary tangles in human upper cervical ganglia. Morphological study with immunohistochemistry and electron microscopy.

Neurofibrillary tangles (NFTs) are one of the main pathological hallmarks of Alzheimer's disease or senile dementia, and are seen in the cerebral cortex and some other nuclei in the central nervous system (CNS). No NFTs have been reported in the human peripheral nervous system, although NFTs were recognized in the dorsal root ganglion of the aged rodents. We report here the presence of NFTs in the upper cervical ganglia (UCGs), but not in the stellate nor in the celiac ganglia, of an elderly patient, who was not demented and had only minimal senile changes in the CNS. Immunohistochemically the antibodies to microtubule-associated protein 2, paired helical filaments and ubiquitin stained positively the NFTs in the UCGs. On electron microscopic examination a periodical twisted pattern of the filaments was identified; these findings suggest that the NFTs of the UCGs have just the same properties as those of the cerebral cortex. This is the first report of the demonstration of NFTs in the peripheral ganglia and might contribute to the study of mechanism of NFT production.

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PubMed1985

Some enkephalin- or VIP-immunoreactive hippocampal pyramidal cells contain neurofibrillary tangles in the brains of aged humans and persons with Alzheimer's disease.

Neurofibrillary tangles are one of the histopathological neuronal abnormalities present in normal aging and especially in Alzheimer's Disease. We have utilized immunocytochemical staining for neuropeptides followed by Congo red with gallocyanin counterstaining and polarized illumination to determine whether enkephalin (Enk), somatostatin (Som), cholecystokinin (CCK), or vasoactive intestinal polypeptide (VIP) are contained in neurons afflicted with such tangles. A few Enk- or VIP-immunoreactive pyramidal cells in field hl and subiculum were found to contain tangles. Many such Enk- or VIP-immunoreactive neurons and cells containing Som- or CCK-like immunoreactivity did not contain such tangles.

Adult↗

PubMed1991

Two distinct types of intraneuronal neurofibrillary tangles highlighted by polarized light after silver impregnation with a modified Bielschowsky method.

Neurofibrillary tangles (NFTs) are one of the morphological hallmarks of Alzheimer's disease. The birefringency and dichroism of NFTs following congo red staining have long been known. Herein, we report the observation that a subset of NFTs show distinct birefringency induced by a modified Bielschowsky silver impregnation method. Birefringency of NFTs could not be elicited after silver impregnation with one other version of the Bielschowsky method or with the Bodian technique. To our knowledge, these properties of NFTs after metal impregnation have not been previously documented.

Alzheimer Disease↗

PubMed1999

Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles.

Combining immunocytochemistry with in situ hybridization of Alzheimer disease (AD) hippocampus demonstrated a 50% reduction in grain density for synaptophysin message over CA1 pyramidal neurons containing neurofibrillary tangles (NFT) relative to near neighbor NFT-free neurons. This decrease was not global, but was selective since message grain density for the lysosomal protein, cathepsin D, increased 33% in these neurons (relative to NFT-free neurons). Poly A+ message grain density decreased by 25% in NFT neurons. Percent of the cell body containing NFT correlated -0.35 (p < 0.0001) with grain density for synaptophysin message. These data verify the concept of altered profiles of gene expression as a function of disease state within single cells and suggest that events associated with NFT formation may lead to altered expression of synaptic messages.

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PubMed1986

Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer's disease: immunohistological studies.

Fractions enriched in neurofibrillary tangles (NFT) and amyloid fibrils were isolated from the cerebral cortex of three cases of senile dementia of the Alzheimer type. Distilled water suspensions of these fractions were excluded from all pore size gels and resisted digestion with various proteolytic enzymes. Formic acid/chloroform treatment of each fraction resulted in the appearance of 4,000-6,000, 15,000-17,000 and 24,000 molecular weight proteins, with concomitant diminution in the amount of excluded material at the top of each gel. The 4,000-6,000 dalton band was best seen in fractions containing randomly arranged amyloid fibrils, and its amino acid composition resembled that of the recently reported "beta" protein. A polyclonal antiserum to purified NFT reacted with tangles in neurons and in dystrophic neurites around plaques by immunoperoxidase staining. No reaction was obtained with cerebrovascular or plaque core amyloid immunohistologically, or with the 4-6 kD protein on immunoblots. Cross-reactivity with the neurofibrillary lesions occurring in Pick's disease, progressive supranuclear palsy, postencephalitic Parkinsonism and dementia pugilistica was also seen. Specific binding of this antiserum to the double filamentous structure was confirmed by immunoelectron microscopy. Although the presence of "beta" protein in both NFT and amyloid-containing fractions suggests that it may be an important constituent of both, cross-contamination cannot be excluded.

Alzheimer Disease↗

PubMed1993

Neuropathologic diagnosis of Alzheimer disease: interrater reliability in the assessment of senile plaques and neurofibrillary tangles.

A diagnosis of definite Alzheimer disease (AD) is made when there is a history of progressive dementia combined with the pathologic findings of numerous senile plaques and neurofibrillary tangles in neocortex. Recent studies have shown, however, that there may be significant interrater variability in the quantitation of these histopathologic lesions. In the present two-center study, interrater reliability and test-retest reliability for plaque and tangle counts were examined when histologic staining and sampling were controlled. We report similar levels of reliability for plaque and tangle counts in 35 cases of AD, nine normal elderly controls and six non-AD dementias: Pearson correlations for interrater reliability ranged from 0.68 to 0.88, and from 0.97 to 0.99 for test-retest reliability. Using quantitative cut-points, concordance between laboratories for experimental diagnoses of AD versus non-AD made on the basis of these lesion counts ranged from 84 to 92% (kappa scores: 0.69-0.84). The agreement between these experimental diagnoses and the clinicopathologic diagnoses of record ranged from 74 to 86% (kappa scores: 0.50-0.71). Thus, under optimal conditions, a moderate to substantial degree of interrater reliability can be attained in the pathologic diagnosis of AD.

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PubMed2003

Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles.

Elevated levels of p25 and constitutive activation of CDK5 have been observed in AD brains. This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs. We examined p25 immunoreactivity in brains from sporadic and familial AD cases, as well as other neurologic diseases that exhibit NFT, such as Down's syndrome (DS), Pick's disease (Pick), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD). Neither the p25 immunoreactivity nor the p25/p35 ratio was elevated in the AD brains or in the other tauopathies (n = 34) compared with controls (n = 11). Although Abeta peptides have been suggested to activate calpain-mediated cleavage of p35 to p25 in cultured neurons, p25 levels in brains of TgCRND8 mice, which express high levels of brain Abeta peptides, were similar to those of non-Tg littermates. Our data suggest that high Abeta levels in brain do not activate p35 proteolysis, and p25 is unlikely to be a causative agent for NFT formation in AD or other tauopathies.

Adult↗

PubMed1995

Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease.

In this report we quantitatively assess the numbers of intracellular and extracellular neurofibrillary tangles (NFT) in the brains of a series of individuals with Alzheimer's disease and of controls and correlate these with neuronal loss. Our data indicate that in some cases, NFT are not removed from the brain throughout the disease process. This finding, together with our previous demonstration of carbonyl-related modifications in NFT, provides additional evidence that the protein constituents of NFT are resistant to proteolytic removal, possibly as a result of extensive cross-links. Additionally, correlation between the number of NFT and neuronal loss indicates that there are at least two distinct mechanisms responsible for neuronal death in Alzheimer's disease that are directly and indirectly related to the presence of neurofibrillary pathology.

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PubMed1992

Racemized D-aspartate in Alzheimer neurofibrillary tangles.

Normal protein-bound L-aspartyl/L-asparaginyl residues may undergo posttranslational modification by racemization to D-aspartate. Based on preliminary results reported here, proteins associated with Alzheimer neurofibrillary tangle preparations contain a greater number of these racemized D-aspartyl residues than the unaffected proteins from the surrounding gray matter or in comparable preparations from normal brains.

Alzheimer Disease↗