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PubMed1990

Neurofibrillary tangles of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease share antigenic determinants with those of Alzheimer disease.

In the Indiana kindred of Gerstmann-Sträussler-Scheinker disease, neurofibrillary tangles (NFT) with paired helical filaments (PHF) are numerous, widespread and consistently present in the cerebral cortex and several subcortical nuclei. Such tangles share antigenic determinants with those of Alzheimer disease; in fact, they are recognized by Alz50, anti-PHF and anti-ubiquitin antibodies. Thus, NFT with structural and immunocytochemical similarities are present in two distinct forms of amyloidosis of the central nervous system, i.e. the Indiana kindred of Gerstmann-Sträussler-Scheinker disease and Alzheimer disease.

Aged↗

PubMed1990

Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons.

In several neurological disorders including Alzheimer's disease, abnormal accumulations of cytoskeleton-associated proteins manifest as neurofibrillary tangles (NFTs) in vulnerable brain regions. Antibodies recognizing tau (5E2 and Alz-50) and ubiquitin epitopes in NFTs were used to examine the influence of glutamate and Ca2+ influx on antigen expression in cultured rat hippocampal neurons. Glutamate caused the degeneration of a subpopulation of pyramidal neurons, which exhibited increased immunostaining with all three antibodies. Subtoxic levels of glutamate also increased 5E2 and Alz-50 antigen levels in a subpopulation of neurons, particularly in the distal regions of the axons. Both glutamate-induced degeneration and increases in tau and ubiquitin immunostaining were prevented by removal of extracellular Ca2+. Increased immunostaining was also induced by Ca2+ ionophore A23187 or elevated levels of extracellular K+. The antigenic changes occurred within 1 hr of exposure to glutamate or A23187 and were not prevented by the protein synthesis inhibitor cycloheximide. These data indicate that Ca2+ influx caused by glutamate can lead to modifications of extant proteins similar to those seen in NFTs.

Animals↗

PubMed1987

Neurofibrillary tangles and the neuronal cytoskeleton.

Antibodies to neurofilaments and the microtubule-associated protein, tau, have been used with anti-paired helical filament (PHF) serum to study Alzheimer neurofibrillary tangles. Tangles and their constituent PHF contain epitopes derived from or cross-reactive with both neurofilaments and tau proteins. These same structures are labelled with anti-PHF antibodies. A component of the anti-PHF serum is against tau proteins. We conclude that PHF are at least in part derived from an abnormal neuronal cytoskeleton.

Alzheimer Disease↗

PubMed1987

Alzheimer's disease: neurofibrillary tangles in nuclei that project to the cerebral cortex.

We have used an antibody to the paired helical filament protein to immunohistochemically identify the regional distribution of subcortical nuclei containing neurofibrillary tangles in brains from Alzheimer's disease patients. Sections were examined from the cerebral cortex, diencephalon, midbrain and pons in seven Alzheimer's and three age-matched normal brains. The antibody sensitively stained the many tangles, and senile plaques, in the cerebral cortex of the Alzheimer's brains and the few tangles and senile plaques in the aged normal cortex. Ten subcortical nuclei contained many tangles in the Alzheimer's brains. The tangles were found not only within the locus coeruleus and dorsal raphe nucleus, which often have been shown to be involved in Alzheimer's neuropathology, but also within several other nuclei not previously related to this disease. For example, tangles were found in the nucleus paranigralis, peripeduncular nucleus, medial parabrachial nucleus and several midline thalamic nuclei. All of the nuclei which contained tangles have been shown, in neuroanatomical tracing studies, to project to the cerebral cortex. These data indicate that Alzheimer's disease is a disease of the cerebral cortex and the numerous subcortical nuclei which diffusely innervate it, and are consistent with the hypothesis that the cerebral cortex is the primary target of the disease and the interconnected subcortical nuclei are secondarily affected due to retrograde transport of a cortical pathogen or failure of normal transport of a trophic agent.

Afferent Pathways↗

PubMed1988

Neurofibrillary tangles and senile plaques in aged bears.

In aged human beings and in individuals with age-associated degenerative disorders, particularly Alzheimer's disease (AD), neurons develop cytoskeletal abnormalities, including neurofibrillary tangles (NFT) and senile plaques (SP). Senile plaques occur in several nonhuman species; however, NFT, with ultrastructural or immunocytochemical similarities to those occurring in humans, have not been identified in other mammals. In this study of five aged bears (Ursus, 20-30 years of age), we identified cytoskeletal abnormalities similar to those occurring in humans. An aged Asiatic brown bear had NFT, composed of straight 10-16-nm filaments, that were immunoreactive with antibodies directed against: phosphorylated epitopes of neurofilaments (NF); tau; A68 (a protein enriched in AD); and an antigen associated with paired helical filaments (PHF). An aged polar bear had numerous SP; neurites of these plaques were immunoreactive with antibodies against phosphorylated epitopes of NF, but NFT were not identified. These results indicate that nonprimate species develop age-related cytoskeletal abnormalities similar to those occurring in humans. Investigations of the comparative pathology of aged mammals may be useful in elucidating the pathogeneses of these abnormalities.

Alzheimer Disease↗

PubMed2000

DNA Damage does not Correlate with Amyloid-beta-Plaques and Neurofibrillary Tangles in Familial Alzheimer's Disease Presenilin-1 [E280A] Mutation.

Recent studies have shown that the missense mutation in presenilin-1 [E280A] increases deposition of amyloid-beta (Abeta) and neurofibrillary tangle (NFT) formation. Indeed, we only observed 10 out of 48 FAD brain sections displaying TUNEL (+) labeling, and none with the classical apoptotic morphology. These results may indicate that DNA fragmentation is not a generalized phenomenon in early-onset FAD PS1 [E280A] patients or that neuronal cells are dying by a different mechanism of cell death. Taking together these findings suggest that Abeta and NFTs are not per se a causative factor to damage neuronal cells but their damage could be more related with individual neuronal vulnerability and brain aging

Journal Article↗

PubMed1989

Sequence of a human MAP-2 region sharing epitopes with Alzheimer neurofibrillary tangles.

Microtubule-associated protein 2 (MAP-2), an abundant neuronal protein, consists of a short microtubule-binding domain and a long projection arm. MAP-2 shares epitopes with Alzheimer neurofibrillary tangles (NFT). However, most anti-MAP-2 antibodies do not stain detergent-extracted NFT, and the role of MAP-2 in NFT formation has therefore been unclear. We have determined the sequence of a 1.7 kb partial MAP-2 cDNA encoding at least three NFT epitopes. The epitopes are not removed by detergent extraction of tangle preparations, suggesting that they are integral components of NFT. Expression vectors containing restriction fragments of the cDNA were used to assign the epitopes to a 51-amino-acid region near the end of the MAP-2 projection arm, distal to the microtubule.

Alzheimer Disease↗

PubMedDate not supplied

Progressive supranuclear palsy with limbic system involvement: report of a case with ultrastructural investigation of neurofibrillary tangles in various locations.

An autopsied case of a 65-year-old woman with progressive supranuclear palsy (PSP) characterized by dementia, hallucination and delirium is described. On neuropathologic examination, widespread neurofibrillary tangles (NFTs) associated with neuronal cell loss and gliosis were observed in the basal ganglia, subthalamic nucleus and various brain stem nuclei, corresponding to the well-established pathology of PSP. In addition, a large number of NFTs with neuronal cell loss were shown in the hippocampus, parahippocampal gyrus, amygdaloid nucleus, subcallosal area, anterior perforated substance, cingulate gyrus and anterior olfactory nucleus. Ultrastructurally, NFTs observed in the periaqueductal central grey, locus ceruleus and hippocampus were composed almost exclusively of straight tubules. On the other hand, those in the amygdaloid and anterior olfactory nuclei were composed mainly of twisted tubules of Alzheimer type. NFTs composed of twisted tubules alone were not observed. The present case was considered as a rare peculiar type of PSP which showed massive systemic appearance of NFTs in the so-called limbic system.

Female↗

PubMed1989

[The reappraisal study of the ultrastructure of Alzheimer's neurofibrillary tangles in three cases of progressive supranuclear palsy].

Progressive supranuclear palsy (PSP) is characterized by symptoms of disturbance of eye movement, nuchal rigidity, parkinsonism and subcortical dementia. Its pathology reveals that Alzheimer's neurofibrillary tangles (NFTs) are situated especially in the nuclei of basal ganglia and brainstem. It has been pointed out that NFTs observed in PSP are composed of straight tubules, the width of which is about 15 nm. This report is to reappraise the ultrastructure of NFTs observed in three cases of PSP. They are case 1; 69-year-old male, case 2; 62-year-old female and case 3; 65-year-old male. The clinical features of three cases were characterized by above-mentioned symptoms. Many NFTs were observed in brainstem of case 1 and 3. NFTs seen in brainstem of case 2 were in a small amount. In case 1 and 2, there were many NFTs in cerebral cortex, especially in parahippocampal gyri and other limbic areas. We examined the portions of frontal cerebral cortex, parahippocampal cortex, the basal nucleus of Meynert, oculomotor nucleus, substantia nigra, pontine nuclei and locus caeruleus of case 1, substantia nigra, red nucleus and inferior olivary nucleus of case 2, and Ammon's horn, globus pallidum, subthalamic nucleus, substantia nigra, oculomotor nucleus, pontine nuclei, locus ceruleus and inferior olivary nucleus of case 3. Ultrastructurally, NFTs of frontal cortex of case 1 consisted of twisted tubules and those of hippocampal and parahippocampal cortices of case 1 consisted of straight and twisted tubules, being observed separately in neurons. The NFTs of brainstem of case 1 and 2 were mainly composed of 12-17 nm straight tubules, and twisted tubules occasionally intermingled with straight components. In locus ceruleus of case 1, a single straight tubule could be seen in the bundles of twisted tubules. NFTs of case 3 were composed of only straight tubules, the width of which was about 15 nm. Twisted components were not observed in neurons of each nuclei of case 3. The characteristic ultrastructure of NFTs in PSP has been an appearance of straight tubules, however, twisted tubules were occasionally observed in this study. There are several case reports which demonstrated an appearance of both straight and twisted components. It is easily presumed that the process of aging takes part in the accumulation of twisted fibrils. However, it is now under consideration why twisted tubules are also observed in PSP. To summarize this study, the cases with many NFTs observed in widespread cerebral cortex may have a tendency to show both straight and twisted tubules.

Aged↗

PubMed1987

A monoclonal antibody that recognizes a phosphorylated epitope in Alzheimer neurofibrillary tangles, neurofilaments and tau proteins immunostains granulovacuolar degeneration.

A monoclonal antibody, raised against extracts from Alzheimer brain, that recognizes a phosphorylated epitope in high molecular weight neurofilament proteins and tau proteins also immunostains Alzheimer neurofibrillary tangles, neurites in senile plaques and granulovacuolar degeneration. This result suggest that granulovacuolar degeneration may contain phosphorylated proteins, possibly due to autophagy of phosphorylated perikaryal proteins that appear to be increased in Alzheimer's disease.

Alzheimer Disease↗

PubMed1983

Immunocytochemical comparison of neurofibrillary tangles in senile dementia of Alzheimer type, progressive supranuclear palsy, and postencephalitic parkinsonism.

Antiserum raised against a two-cycle-purified human brain microtubule fraction that binds specifically to tangles of senile dementia of the Alzheimer type was tested on the subthalamus, basis pontis, and midbrain sections of two patients with progressive supranuclear palsy. Tangles composed of 15 nm straight fibers in these areas showed positive immunolabeling with the antiserum. The labeling tangles appeared as a fibrous meshwork in neuronal cell bodies and occasionally in short segments of axons. Corresponding sections of brains obtained from patients with idiopathic parkinsonism, striatonigral degeneration, and olivopontocerebellar atrophy treated with the same antiserum did not display peroxidase products. Only in the elderly subjects and patients with postencephalitic parkinsonism did the periaqueductal gray and median raphe show occasional cells that reacted positively with the antiserum. Tangles in the substantia nigra of patients with postencephalitic parkinsonism were also recognized by the antiserum. The results suggest that the two morphologically distinct neurofibrillary tangles share their immunological properties with components present in microtubule fractions of normal brain.

Aged↗

PubMed1990

Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles.

A man, aged 58 years, suffered from progressive dementia, parkinsonism, and gaze paralysis for 30 months. Autopsy revealed severe degeneration of the substantia nigra, numerous swollen chromatolytic neurons within the cerebral cortex, scattered basal neurofibrillary tangles, and gliosis of the cerebral white matter and basal ganglia. Unusual globular inclusions positive for tau protein were detected within neurons of the upper cortical layers. Although the pathological findings were comparable with corticonigral degeneration with neuronal achromasia, several clinical and pathological features characteristic for progressive supranuclear palsy, progressive subcortical gliosis, and Pick's disease in this and the nine previously reported cases hampered the unequivocal nosological placement.

Basal Ganglia↗

PubMed1976

Neurofibrillary tangles in the dementia of "normal pressure" hydrocephalus.

Routine neuropathological examination could not explain the dramatic improvement exhibited by one patient with "normal pressure" hydrocephalus after shunting. The improved patient contrasted remarkably with the unchanged condition of four others also shunted successfully. The five brains were analysed by quantitative morphometry to determine the degree of neurofibrillary tangle formation in mesial temporal neurons. The density of tangle-bearing nerve cells in the four unimproved cases was markedly greater than in age-matched control brains from nineteen normal subjects, and fell in the same range as that of eight dements with neuropathologically confirmed Alzheimer's disease. The density of the one who recovered was within normal limits. The duration of dementia before shunting, and the total duration of dementia in these five patients rank in the same order as their degree of neurofibrillary formation. Furthermore, a positive linear correlation exists between the Tangle Indices and the total duration of dementia. The data suggest that early diagnosis may improve the chances of reversing the dementia of normal pressure hydrocephalus before histological alterations prove too severe.

Aged↗

PubMed1990

Glial fibrillary acidic protein and beta A4 protein deposits in temporal lobe of aging brain and senile dementia of the Alzheimer type: relation with the cognitive state and with quantitative studies of senile plaques and neurofibrillary tangles.

The aim of this study was to compare brain glial fibrillary acidic protein (GFAP) levels to the modifications of cognitive functions (Blessed test score [BTS]), the density of the main neuropathological lesions (senile plaques [SP] and neurofibrillary tangles [NFT]), and the density of the two main subtypes of beta A4 deposits (classic plaques and diffuse deposits) in a series of patients with normal aging and senile dementia of the Alzheimer type of various degrees of severity. GFAP levels (enzyme-linked immunosorbent assay [ELISA] technique) and the densities of changes were measured in the temporal lobe of 12 women over 75 years of age. Under these conditions, the ELISA assay could determine GFAP in brain homogenates (aqueous-Triton buffer soluble extract) in a range from 2.5 ng to 600 ng per assay. Least affected patients (with a BTS of 19 and over) all ranged below 60 micrograms/mg protein. Most affected patients (with a BTS under 6) ranged above 150 micrograms/mg protein. However, interindividual variations were wide. A significant correlation between the BTS and the amount of GFAP could be found only when using the non parametric test of Spearman. There was a significant positive correlation between the amount of GFAP and the density of 1) SP, 2) NFT both revealed by Bodian's silver stain, and 3) classic beta A4 plaques shown by immunocytochemistry. On the contrary, no correlation was observed with diffuse beta A4 deposits. One case with very large amounts of diffuse beta A4 deposits without SP or NFT showed no associated GFAP reactivity. This suggests that GFAP production is a critical event in the formation of classic SP.

Aged↗

PubMed1991

Neurofibrillary tangles and histamine-containing neurons in Alzheimer hypothalamus.

The location of histamine-immunoreactive (IR) cell bodies in normal aged human brain and in cases of Alzheimer's disease (AD) were compared to the distribution of neurofibrillary tangles (NFT). Cryostat sections were fixed with carbodiimide and processed for histamine-immunohistochemistry using the PAP technique. NFT were visualized in the same sections using thioflavin. Histamine-IR cell bodies in human brain were concentrated in the tuberomammillary (TM) nucleus that embodied a major part of the hypothalamus. Although located in similar large profiles and mainly concentrated in the TM area, the numerous hypothalamic NFT in AD were seldom found within the histamine-IR neurons.

Aged↗

PubMedDate not supplied

A comparative study of modified Bielschowsky, Bodian and thioflavin S stains on Alzheimer's neurofibrillary tangles.

Serial sections of the brains of two cases with Alzheimer's disease were stained with the standard Bodian, modified Bielschowsky (reformed Gros-Schultze's modification) and thioflavin S methods. The numbers of demonstrated Alzheimer's neurofibrillary tangles (NFTs) were different between the two silver stains: from 15 to 75% more NFTs were shown and more distinctly with the modified Bielschowsky stain than with the Bodian stain. Many of the NFTs in both cases were of eosinophilic and less argentophilic type. Although the NFTs were not counted, the thioflavin S stain seemed to have no apparent advantage over the modified Bielschowsky stain in the demonstration of NFTs.

Aged↗

PubMed1986

A cDNA for a human microtubule associated protein 2 epitope in the Alzheimer neurofibrillary tangle.

Microtubule associated protein 2 (MAP2) forms a long outward projection from the microtubule wall and is localized to the microtubule population of neuronal cell bodies and dendrites. In Alzheimer's disease, MAP2 epitopes are shared with the neurofibrillary tangle (NFT). Direct information about the molecular composition of the NFT can be obtained by cloning the genes for protein epitopes shared with NFT. Using two monoclonal antibodies to distinct MAP2 epitopes, one of which recognizes NFT, we screened a complex human fetal brain cDNA expression library constructed in lambda gt11. A 2.4 kilobase (kb) cDNA reacted with both antibodies independently. Northern blot analysis showed hybridization of the clone to a 9 kb RNA specific not only to brain but also to neurons. The DNA sequence of the cDNA will include the information for the MAP2 epitope contained in NFT.

Alzheimer Disease↗

PubMed1982

Two autopsy cases of Pick's disease with neurofibrillary tangles.

Two cases of presenile dementia were presented. Both showed "stehende Redensarten" and aphasia. Histopathologically, besides Pick features--temporal lobe atrophy, fibrillary gliosis of the temporal white matter and neuronal loss in the 2--3 cortical layers--, Alzheimer features--neurofibrillary tangles and granulo-vacuolar degeneration--were found in both cases. But no senile plaques were found. Pseudocalcerous deposits were observed in the cerebral cortex, basal ganglia and cerebellum. Atypical cases with both Pick's and Alzheimer's diseases in the literature were classified into four groups according to the extent of the features of each disease. Sensory aphasia, which is relatively unusual in Pick's disease, was correlated to the atrophy of left T1, and similar cases in the literature were reviewed.

Alzheimer Disease↗