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PubMed1993

Neurofibrillary tangles of Guamanian amyotrophic lateral sclerosis, parkinsonism-dementia and neurologically normal Guamanians contain a 4- to 4.5-kilodalton protein which is immunoreactive to anti-amyloid beta/A4-protein antibodies.

Neurofibrillary tangles (NFT), one of the neurodegenerative features of Alzheimer's disease, Down's syndrome and normal aging, is a constant, widespread neuropathological finding in Guamanian amyotrophic lateral sclerosis (ALS), parkinsonism-dementia (PD) and in neurologically normal Guamanians, dying of causes other than ALS and PD. NFT in brain tissue sections of patients with Guamanian ALS and PD were immunoreactive to antibodies directed against a 43-amino acid synthetic peptide homologous to amyloid beta/A4-protein (anti-SP43) associated with Alzheimer's disease. NFT extracted from frozen brain tissues of Guamanian patients with ALS and PD and from tissues of neurologically normal Guamanians were congophilic and birefringent. By negative-stain electron microscopy, NFT preparations contained bundles and/or isolated single, straight, unpaired filaments in Guamanian ALS and occasionally pairing of filaments in neurologically normal Guamanians, measuring 5-20 nm in diameter. Formic acid digestion of NFT preparations, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size-exclusion high-pressure liquid chromatography, showed a protein with an apparent molecular mass of 4- to 4.5-kDa, which by Western blot analysis was immunoreactive to anti-SP43. Immunoabsorption of purified NFT or SP43 with anti-SP43 abolished immunostaining. Our study corroborate previous data that amyloid beta/A4-protein is present in NFT in Guamanian PD. Furthermore, our data indicate that amyloid beta/A4-protein is present in NFT in brain tissues of patients with Guamanian ALS and in neurologically normal Guamanians, suggesting a common mechanism of amyloidogenesis with NFT formation in Alzheimer's disease and normal brain aging.

Amyloid beta-Peptides↗

PubMedDate not supplied

Progressive formation of neuritic plaques and neurofibrillary tangles is exponentially related to age and neuronal size. A morphometric study of three geographically distinct series of aging people.

Neuronal size and the incidence of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were morphometrically and quantitatively studied in the entorhinal cortex of 300 autopsied individuals without dementia in three geographically distinct series (Brazil, Germany and Japan), and an additional series including 30 clinically diagnosed Alzheimer's disease patients. The mean ages at onset of NPs and NFTs were similar between the three normal series, and the incidence of NPs and NFTs increased exponentially with age, but at different rates. A correlation was found between larger neuronal size and higher incidence of NPs and NFTs. Neuronal size distribution largely seemed to account for the differences between the series. While the onset of neurodegeneration may be tightly programmed, i.e., in a species-specific manner, our data support the idea that the incidence of NPs and NFTs and the progression from NPs to NFTs may vary remarkably, depending on neuronal size.

Adult↗

PubMed1993

Comparison of silver stainings and immunohistology for the detection of neurofibrillary tangles and extracellular cerebral amyloid in paraffin sections.

The sensitivities of six silver-staining methods and immunohistology for beta and tau protein were compared for their ability to demonstrate neurofibrillary tangles (NFT) and senile plaques (SP) in paraffin sections. Serial sections of the hippocampal area of 35 brains showing these neuropathological findings were cut and stained by the methods of Cross, Campbell, Bielschowsky, Gallyas, Yamaguchi, our variant (method of Reusche) and immunohistology. In the detection of NFT, the techniques of Gallyas, Bielschowsky, our method and tau protein immunostaining were the most sensitive methods. The procedure of Campbell and again our method were proven to be superior to the other stainings in demonstrating SP as well as diffuse and subpial amyloid. Moreover, our method reliably stained vascular and perivascular amyloid which can be identified in brains with congophilic angiopathy. Due to a lack of control in certain steps of the procedures most of the silver-staining methods are complicated and to not present reliable results. Our variant is easy to perform and, thus, may be used as a sensitive, simple and reliable alternative for the impregnation of the main lesions (NFT and SP) occurring in senile dementia of Alzheimer type and brains with normal aging for screening, retrospective and quantitative studies and for routine purposes.

Aging↗

PubMed1995

Characterization of the association of phospholipase C-delta with Alzheimer neurofibrillary tangles.

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. We have previously demonstrated that an antibody to the PLC isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of AD patients [Am. J. Pathol., 139 (1991) 737-742]. To clarify the crucial involvement of abnormal PLC-delta accumulation contributing to the formation of NFT, we performed light and electron microscopic immunocytochemistry. To determine PLC-delta's association with NFT, its resistance to solubilization was also studied. Anti-PLC-delta antibody marked the same NFT-bearing neurons containing tau immunoreactivity with tau more clearly on NFT filaments and PLC-delta covering it superficially at the light microscope level. The double stained preparations with anti-PLC-delta antibody and bFGF binding suggested that PLC-delta is an intracellular marker and is not retained after neuronal death. Employing immunoperoxidase and immunogold electron microscopic immunocytochemistry, we found that the antibody to PLC-delta reacts mostly with amorphous granular materials, and occasionally with some abnormal filaments within NFT. Nevertheless, PLC-delta in NFT was resistant to removal by high salt or ionic detergent, indicating it is an integral NFT component. These results indicate that antigenic determinants unique to PLC-delta are mainly present intraneuronally on the amorphous granular components of NFT as well as the abnormal filaments, suggesting PLC-delta's interactions and possible role in the formation of intraneuronal filamentous inclusions in AD.

Aged↗

PubMed1993

Beta-amyloid protein precursor and tau mRNA levels versus beta-amyloid plaque and neurofibrillary tangles in the aged human brain.

To learn whether or not the levels of beta-amyloid protein precursor (APP) and tau mRNAs are related to the formation of beta-amyloid and neurofibrillary tangles, we quantified these mRNA levels in three cortical regions of 38 aged human brains, which were examined immunocytochemically for beta-amyloid and tangles. Marked individual variabilities were noted in APP and tau mRNA levels among elderly individuals. The mean APP mRNA level was slightly reduced in the beta-amyloid plaque (+2) group, but not in the plaque (+) group, compared to the plaque (-) group. Some brains in the plaque (-) group showed increased APP expression, the extent of which was not seen in the plaque (+) or (+2) group. The differences in the mean tau mRNA levels were not statistically significant among the tangle (-), (+), and (+2) groups. These results show that beta-protein and tau deposition do not accompany increased expression of the APP and tau genes, respectively, and thus suggest that factors other than gene expression may be at work in the progression of beta-amyloid and/or tangle formation in the aged human brain.

Aged↗

PubMed1997

The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease.

We measured tau concentrations in cerebrospinal fluid (CSF) samples taken during the lifetime of 43 patients with Alzheimer's disease (AD) and correlated these values with neurofibrillary tangle (NFT) scores as well as glial fibrillary acidic protein (GFAP) expression as a marker of astrocytosis in the brain post-mortem. The CSF tau values showed a positive correlation with neocortical NFT scores (r = 0.44, p < 0.005), while GFAP immmunoreactivity did not correlate with CSF tau. This study reveals a high variation in CSF tau values in patients with neuropathologically confirmed AD (range 194-1539 pg/ml) and indicates that high CSF tau values in the late phase of Alzheimer's disease predict severe neurodegeneration as evidenced by increased NFT scores.

Aged↗

PubMed1993

Striatonigral degeneration with neurofibrillary tangles.

An autopsy was performed on a 48-year-old woman with clinical features of parkinsonism-plus syndrome with dominating akinesia. Neuropathological examination revealed striato-nigral degeneration (SND) and neurofibrillary tangles (NFT) characterizing progressive supranuclear palsy. Such an unusual combination of pathological findings may constitute a distinct clinico-pathological entity, with akinesia as the main clinical symptom, and with a pathological substrate of SND and NFT. We suggest that such cases may establish a separate variant within multisystem atrophies syndromes.

Adult↗

PubMedDate not supplied

A 14-year-old patient with Ewing's sarcoma presenting at autopsy with multiple neurofibrillary tangles and Lewy bodies in addition to hemiatrophy of the central nervous system.

The autopsy findings of a 14-year-old Japanese girl with Ewing's sarcoma, who had multiple neurofibrillary tangles and Lewy bodies and hemiatrophy of the central nervous system (CNS), are reported. She had retinoblastoma of her right eye 8 months after birth, which was treated with chemotherapy and irradiation (40 Gy), twice, seizures 1 year and 2 months after birth, and thereafter severe mental retardation. She showed left hemiparesis after a febrile seizure at the age of 7 years and CT disclosed the right cerebral hemiatrophy. For the last 2 years of life she suffered from Ewing's sarcoma. Extrapyramidal signs were absent. Neuropathologically, tangles consisting of paired helical filaments were distributed symmetrically in virtually all the grey matter. They were particularly numerous in the frontal cortex and substantia nigra, but sparse in the nucleus of Meynert, hippocampus, and brainstem. Several Lewy bodies, which were ultrastructurally identical to those seen in Parkinson's disease, were present in the substantia nigra (more on the left than right) and locus coeruleus. Morphometrically, the number and size of substantia nigral neurons were reduced, the reduction in the latter being more marked than the former, but the melanin pigment contents and shapes of the remaining neurons appeared normal. The right cerebral hemiatrophy with contralateral cerebellar hemiatrophy may have been attributable to irradiation. Although our patient did not have parkinsonism, her features resembled those of a 28-year-old autopsy case reported by Popovich et al. [1987].

Adolescent↗

PubMed1997

Low prevalence of apolipoprotein E epsilon 4 allele in the neurofibrillary tangle predominant form of senile dementia.

Apolipoprotein E (apoE) genotypes were analyzed in a subset of demented very old patients who share a uniform neuropathological picture consisting of various numbers of neurofibrillary tangles (NFT) in allocortical areas of the inferomedial temporal lobe without significant numbers of either diffuse amyloid or neuritic plaques. Among 18 patients with this condition referred to as NFT-predominant senile dementia (average age at death 87 +/- 4.7 years), we found allele frequencies of 0.11 epsilon 2, 0.86 epsilon 3 and 0.03 epsilon 4, which are significantly different from allele frequencies reported in Alzheimer's disease (0.04 epsilon 2, 0.59 epsilon 3 and 0.38 epsilon 4). The low prevalence of the apoE epsilon 4 allele in this subset of patients is striking and suggests that NFT-predominant senile dementia is a dementing neurodegenerative disease in which the deposition of A beta-amyloid did not occur, possibly due to protective effects of epsilon 2 and/or epsilon 3 alleles or lack of a promoting effect of apoE epsilon 4 on amyloidogenesis. We propose that NFT-predominant dementia is a variant of Alzheimer's disease occurring in the very old.

Aged↗

PubMed1988

Isolation and characterization of cDNA clones encoding epitopes shared with Alzheimer neurofibrillary tangles.

A pool of ten monoclonal antibodies to SDS-insoluble epitopes of Alzheimer neurofibrillary tangles (NFT) was used to screen an adult human brain cDNA expression library. Fourteen clones were isolated, two of which are described. The largest of the clones encodes 80 kD, or approximately 600 amino acids, of microtubule-associated protein 2 (MAP 2). The MAP 2 region encoded by the clone shares at least two epitopes with human tau, another microtubule-associated protein which cross-reacts with NFT. In rat brain mRNA, the MAP 2 cDNA hybridizes to a single transcript of 9.5 kb. In human neuroblastoma mRNA, the MAP 2 cDNA hybridizes, at high stringency, to two transcripts of 9.5 kb and 6 kb. The 6-kb transcript comigrates with the transcript for tau, as detected by a human tau cDNA. The properties of the MAP 2 cDNA suggest that, in humans, MAP 2 and tau have a common domain which may play a role in NFT formation. Another clone isolated with the anti-NFT antibodies shares epitopes, but not nucleic acid homology, with the MAP 2 cDNA. This clone detects a single abundant transcript of 1 kb present in RNA from human neuroblastoma and from several non-neuronal human cell lines. The properties of this cDNA suggest that it encodes a protein other than those previously reported to cross-react with NFT.

Adult↗

PubMed1990

Induction of epitopes associated with neurofibrillary tangles in clonal mouse neuroblastoma (S20Y) cells.

Accumulation of paired helical filaments (PHF) in neurofibrillary tangles is a key neuropathological hallmark in Alzheimer's disease (AD). To date, PHF have been found primarily in humans. Cultured murine cholinergic neuroblastoma (S20Y) cells, following exposure to a serum-free medium or a differentiation medium, developed immunoreactivity to anti-PHF antibodies, and to the Alz-50 by immunocytochemical and immunoblot analyses. Electron microscopic examination revealed abundant fascicles of 10-nm filaments coursing tortuously amongst organelles, such as mitochondria, endoplasmic reticulum and dense-core vesicles, in perikarya and in neuritic extensions. However, subcellular structures identical or similar to PHF could not be found in these non-human cells. This convenient cell culture model may prove to be useful for studying certain aspects of the mechanisms underlying the abnormal cytoskeletal alterations which are characteristic of AD and related neurodegenerative disorders.

Alzheimer Disease↗

PubMed1981

Distribution and ultrastructure of Alzheimer's neurofibrillary tangles in postencephalitic Parkinsonism of Economo type.

The distribution and ultrastructure of Alzheimer's neurofibrillary tangles (ANT) in the brain stem, hypothalamus, and Ammon's horn were studied in four patients with postencephalitic parkinsonism of Economo type (PEPE). The distribution of ANT was as previously reported; the pattern of distribution resembled to that of amine-containing nerve cells. Ultrastructurally, ANT revealed twisted tubules (TT), but straight tubules (ST) of 150 A width were also found in the locus ceruleus of three cases; sometimes, TT and ST were mixed in a single neuron. Whether the coexistence of TT and ST in the locus ceruleus is a characteristic ultrastructural feature of ANT in PEPE or a regional peculiarity could not be determined. Ultrastructurally, ANT in PEPE were identical to those found in the brains of patients with Alzheimer's disease or senile dementia.

Aged↗

PubMed1987

Two monoclonal antibodies recognize Alzheimer's neurofibrillary tangles, neurofilament, and microtubule-associated proteins.

Two monoclonal antibodies that recognize Alzheimer's neurofibrillary tangles (ANTs), AD10 and AB18, have been characterized by immunoblotting against human and calf spinal cord neurofilament (NF) and calf brain microtubule preparations. Both antibodies bind to the 200-kilodalton (kd) (NF-H) and 160-kd (NF-M) but not to the 68-kd (NF-L) NF triplet proteins. They also bind to high-molecular-weight microtubule-associated proteins (MAPs) and tau. AD10 immunostains MAP2 and MAP1 families, whereas AB18 stains mainly MAP1 bands. Preincubation of intact filament preparation or nitrocellulose strips containing electroblotted NF proteins with Escherichia coli alkaline phosphatase completely blocks AD10 binding and partially blocks binding of AB18. These results suggest that the determinants recognized by these antibodies are phosphorylated. Immunoblotting of peptide fragments generated by limited proteolysis of NF proteins with alpha-chymotrypsin and Staphylococcus aureus V8 protease shows that the localization of the antigenic determinants to AD10 and AB18 in NF-H is approximately 100 and 60 kd, respectively, away from the carboxy terminal, a region previously shown to form the NF projection side arm. In NF-M, the antigenic determinants to both antibodies are located also in the projection side arm, in a 60-kd polypeptide adjacent to the alpha-helical filament core. The results show that ANTs contain at least two phosphorylated antigenic sites that are present in NF and MAPs, a finding suggesting that ANTs may be composed of proteins or their fragments with epitopes shared by cytoskeletal proteins.

Alzheimer Disease↗

PubMed1996

Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients.

The apolipoprotein E genotype and cortical senile plaque (SP) and cortical and hippocampal neurofibrillary tangle (NFT) densities were determined in non-demented individuals and neuropathologically confirmed AD patients. The non-demented population was further subdivided according to presence or absence of pathologically established critical coronary artery disease (cCAD), hypertension (HyperT), or neither (non-heart disease; non-HD). The apolipoprotein E4 (APOE4) allele incidence and dose frequencies were increased in the AD, cCAD and HyperT groups compared to the non-HD controls. The mean number of SP and NFT was significantly increased with the presence of the APOE4 allele within the entire population. After grouping the non-demented subjects according to cardiac status, SP but not NFT density was increased among those individuals with the APOE4 genotype. In HyperT, the increased density of SP also correlated to the APOE4 allele dose frequency. The density of SP and NFT was increased in all regions of AD brain compared to all other non-demented groups, but no significant difference was found between AD patients with or without an APOE4 allele. These two AD groups were age-matched, but could not be matched for disease duration. The data suggest a relationship between heart disease, APOE4 genotype and the presence of SP regardless of cognitive status.

Aged↗

PubMed1994

Demonstration of neurofibrillary tangles and neuropil thread-like structures in spinal cord white matter in parkinsonism-dementia complex on Guam and in Guamanian amyotrophic lateral sclerosis.

This report concerns the demonstration and distribution of neurofibrillary tangles (NFTs), immunoreactive neuropil thread-like structures and dots in the spinal cord gray and white matter of six patients with parkinsonism-dementia complex on Guam and five patients with Guamanian amyotrophic lateral sclerosis (ALS). A monoclonal antibody to Alzheimer NFTs was used. NFTs were found in the spinal cord gray matter and white matter and all patients had immunoreactive neuropil thread-like structures and dots in the gray matter as well as in the white matter. They were particularly numerous in the lateral funiculus of patients with Guamanian ALS.

Amyotrophic Lateral Sclerosis↗

PubMedDate not supplied

Quantitative analysis of lipofuscin and neurofibrillary tangles in the hippocampal neurons of Alzheimer disease brains.

Using computer-enhanced image analysis, the amount of lipofuscin was measured in 500 hippocampal pyramidal neurons (regions CA2 and CA3) with and without neurofibrillary tangles (NFT), in brains of 10 patients with Alzheimer's disease (AD), as well as in 6 age-matched controls. The average content of lipofuscin in those cells from AD brains carrying NFT is only 10% of the total perikaryal area, whereas in the AD neurons free of NFT, and in age matched controls, lipofuscin amounted to 31 and 33% of cellular area, respectively. Measurements of lipofuscin's intrinsic autofluorescence confirmed this material to be three times more abundant in AD neurons without NFT and in controls. We propose that a breakdown in the capacity for making lipofuscin may result in the neuronal inability to store toxic waste. Such a defect could be responsible for the generation of NFT and ultimately may contribute to neuronal demise.

Aged↗

PubMed2002

Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains.

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.

Aged↗

PubMed1998

Scanning electron microscopical study of neurofibrillary tangles in a presenile patient with Down's syndrome.

An autopsy case of a 64-year old woman with Down's syndrome (DS) is reported with a special reference to the ultrastructure of neurofibrillary tangles (NFTs). NFTs and senile plaques were diffusely observed throughout the brain. The most severe changes were seen in the amygdaloid nuclear complex and hippocampus. Immunohistochemistry of the NFTs and senile plaques indicated the features identical to those in Alzheimer's disease (AD). Ultrastructurally, NFTs were composed of straight filaments and two profiles of paired helical filaments (PHFs). By transmission electron microscopy, straight filaments measured 25-28 nm in diameter. As to the PHFs, one type was 33 nm in maximum diameter and constricted at a 75- to 80-nm interval. The other was 16-18 nm in maximum diameter and constricted at a 35- to 40-nm interval. By scanning electron microscopy, the diameter of the straight filaments measured up to 28-30 nm. Two profiles of PHFs were observed. One type of PHF showed thick filaments about 34 nm in maximum diameter and constrictions at an 80-nm interval. The other was about 17 nm in diameter and constricted at a 40-nm interval. The helical directions of both PHFs were left-handed. The frequency of PHFs with short interval was much higher in DS than AD. Furthermore, the length of the periodicity of this type of PHF was somewhat less than that of AD. Thus, these findings suggest that the neuropathological changes in DS and AD share a common etiopathology, but that some differences in the PHFs between DS and AD may reflect on molecular difference in the proteins or peptides associated with PHF formation.

Alzheimer Disease↗