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At least 19 recordsLinked to original sources
PubMed2002

Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles.

Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase that, when activated, induces neurite outgrowth. Recent in vitro studies have shown that cdk5 phosphorylates tau at serine 199, serine 202, and threonine 205 and that p25, an activator of cdk5, is increased in Alzheimer disease (AD). Since tau is hyperphosphorylated at these sites in neurofibrillary tangles, we examined brain tissue from patients with AD and normal elderly control cases to determine whether cdk5 and these phosphoepitopes colocalize in neurofibrillary tangles. Adjacent temporal lobe sections were double immunostained with a polyclonal anti-cdk5 and monoclonal AT8 (which recognizes phosphorylated serine 199, serine 202, and threonine 205 in tau) antibodies. A subset of AT8 phosphotau-positive neurons was immunoreactive for cdk5 in entorhinal (area 28) and perirhinal (area 35) cortices and CA1 of the hippocampus. We assessed the ratio of cdk5-positive cells to AT8-positive cells and found that there is a higher degree of colocalization in pre-neurofibrillary tangles as opposed to intraneuronal and extraneuronal neurofibrillary tangles. We further examined colocalization using fluorescence resonance energy transfer. This suggests a close, stable intermolecular association between cdk5 and phosphorylated tau, consistent with phosphorylation of tau by cdk5 in AD brain.

Aged↗
PubMed1989

A4 amyloid protein immunoreactivity is present in Alzheimer's disease neurofibrillary tangles.

Neurofibrillary tangles and neuritic plaques are the neuropathological hallmarks of Alzheimer's disease. The latter consist of a core of A4 amyloid protein. We now report that some neurofibrillary tangles ('tombstone tangles') are also A4 immunoreactive. This observation is consistent with the hypothesis that A4 amyloid accumulation is a component of both neurofibrillary tangles and neuritic plaques.

Alzheimer Disease↗
PubMed1992

What's new in the pathology of neuronal cytoskeleton: the significance of neurofibrillary tangles.

Neurofibrillary tangles are a neuronal change observed in various conditions, linked with dementia when affecting the cerebral cortex as in Alzheimer's disease. They may be found locally close to fibrous or vascular tumors, or affect extensive regions of the neocortex while the cerebellum and the medulla are not affected. Recent immunological and biochemical studies demonstrate that the MT-associated protein tau is the main component of the tangles, in an abnormally phosphorylated state. A consequence of the formation of tangles is a decreased assembly of MT in axons and dendrites, with disturbances of neuroplasmic flow. The relations between tangles and amyloid, as seen in Alzheimer's and Down's diseases are topographical, tangles accumulating in particular in neurites close to the amyloid in the senile plaques (but also at distance in cell bodies and neurites). Genetically and biochemically A4 or beta-amyloid and tau differ. The exact relation between the beta-pleated proteins of tangles and amyloid remain poorly understood.

Amyloid beta-Peptides↗
PubMed1991

The hypothesis of zinc deficiency in the pathogenesis of neurofibrillary tangles.

Neurofibrillary tangles (NFT) in human encephalopathies of various etiologies may result from a common pathogenetic mechanism: a functional zinc decrease leading to a deficiency of the DNA metabolizing zinc-enzymes, giving rise to abnormal neuronal DNA and synthesis of pathological proteins: NFT. In encephalopathia Saturnica, zinc decreases in the hippocampus displaced by lead; in Guam's encephalopathy, calcium deficiency permits the entry in the brain of toxic metals that may displace zinc; in Boxer's dementia and some viral encephalitides, blood-brain-barrier (BBB) is altered and abnormal metals may reach the brain; in Down's syndrome and Alzheimer's disease precapillary and capillary amyloidosis disturbs the BBB, metals (iron and aluminium) are encrusted in the amyloid and their brain level increases, whereas zinc decreases especially in the hippocampus. A deficiency of the zinc enzymes of neuronal detoxication, of glutamate catabolism and of some neurotransmitters metabolisms may also contribute in the neuronal dysfunction of these encephalopathies. A non-toxic zinc compound crossing the BBB may be useful for the treatment of these encephalopathies and especially for Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

Argyrophilic grains are not always argyrophilic--distinction from neurofibrillary tangles of diffuse neurofibrillary tangles with calcification revealed by comparison between Gallyas and Campbell-Switzer methods.

Silver staining profiles of argyrophilic grains (AGs) and of neurofibrillary tangles (NFTs) of diffuse neurofibrillary tangles with calcification (DNTC, collectively as DNTC-NFTs) were examined for their relation to tau- and ubiquitin-like immunoreactivity (IR). Pairs of mirror sections were triple-fluorolabeled with an anti-PHF tau (AT8) antibody, an anti-ubiquitin antibody and thiazin red (TR), a fluorochrome that identifies fibrillary structures such as NFTs of Alzheimer's disease (AD). One of the paired sections was subsequently stained with Gallyas method (GAL), and the other with Campbell-Switzer method (CS). Comparison of the same microscopic field on the paired fluorolabeled sections, subsequently silver-stained with either GAL or CS enabled the determination of five different profiles of each structure: AT8-IR, ubiquitin-like-IR, affinity to TR, argyrophilia with GAL or CS staining. AGs, mainly composed of four-repeat (4R) tau, were argyrophilic with GAL but not with CS, and their affinity to TR and ubiquitin-like-IR was not intense. This staining profile of AGs is identical with those of tau-positive structures in the cortex of progressive supranuclear palsy/corticobasal degeneration, both composed of 4R tau. This selective affinity of AGs to GAL is in sharp contrast with Pick bodies, composed of three-repeat (3R) tau, that are positive for CS but not for GAL, as we reported previously. This contrast is explainable if the argyrophilia with CS is related to deposits containing 3R tau, while that with GAL is linked to those containing 4R tau. Indeed, DNTC-NFTs, that contain both 3R and 4R tau, were argyrophilic with CS and GAL, and their affinity to TR and ubiquitin-like-IR were consistent, as we reported previously for NFTs of AD and of Down's syndrome, both similarly composed of 3R and 4R tau. Taken together, differences in molecular composition of tau protein in these deposits are linked to their argyrophilic properties dependent on the staining method in these sporadic tauopathies. Although explanations for these empirical differences are not yet available, awareness of this clear distinction is potentially of diagnostic and pathological significance.

Aged↗
PubMed1984

Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles.

Neurofibrillary tangles (NFT) are the principal structural alteration of neuronal cell bodies in Alzheimer disease as well as in normal aging of the human brain. While the ultrastructure of these intraneuronal lesions has been extensively studied, the biochemical composition of the fibers comprising the NFT is unknown. We report the production of three monoclonal antibodies against the microtubule-associated protein 2 (MAP-2), one of which intensely labels Alzheimer NFT. All three antibodies specifically recognize MAP-2 on immunoblots and stain brain tissue in a characteristic dendritic pattern. The three antibodies are directed against at least two different antigenic sites on the MAP-2 molecule, and one appears to recognize a phosphorylation site on MAP-2. That only one of the three antibodies immunolabels NFT suggests that the formation of the tangle involves some modification of the MAP-2 molecule. Our findings suggest that one aspect of Alzheimer-type neurofibrillary pathology is an aggregation of MAP-2 or MAP-2 fragments with altered neurofilamentous elements present in NFT. Normal interactive function, which putatively occurs between neurofilaments and MAP-2, may thus be disrupted in Alzheimer disease.

Alzheimer Disease↗
PubMed1991

Ultrastructural localization of beta-amyloid, tau, and ubiquitin epitopes in extracellular neurofibrillary tangles.

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer disease, are commonly located in perikarya of neurons. In advanced cases of Alzheimer disease, however, NFTs are observed also in the extracellular space. As extracellular NFTs (E-NFTs), and occasionally intracellular NFTs (I-NFTs), are recognized by antibodies to beta-amyloid protein (beta AP), beta AP may be present not only in amyloid deposits but also in paired helical filaments (PHFs), the primary components of NFTs. We compared the antigenic characteristics of I-NFTs and E-NFTs with light- and electron-microscopic immunocytochemistry by using several antibodies to noncontiguous epitopes of the microtubule-associated protein tau and of ubiquitin (Ub) as well as an antiserum to beta AP. At variance with I-NFTs, E-NFTs were made predominantly of straight filaments (SFs), rather than PHFs, that were often separated by astroglial processes and in close association with small beta AP deposits. Occasionally, E-NFTs were made of bundles of amorphous material, which showed no resemblance to SFs, PHFs, or amyloid fibrils. The antigenic changes in E-NFTs suggest that when NFTs become extracellular they lose the N and, possibly, the C termini of tau while maintaining the intermediate region of the molecule; they also lose the N-terminal two-thirds of Ub while the C-terminal conjugation site of Ub is preserved. A small subset of E-NFTs reacted with antibodies to both beta AP and tau. Although in most E-NFTs, the epitopes recognized by tau and Ub antibodies were located in typical PHFs and SFs, the epitopes recognized in this subset of anti-beta AP and anti-tau-positive E-NFTs were located exclusively in the bundles of amorphous material. It is suggested that either beta AP epitopes are present but inaccessible in PHFs and SFs and become exposed after conformational changes occurring in the extracellular space or PHFs and SFs become closely associated with beta AP in the extracellular space.

Alzheimer Disease↗
PubMed1990

Relative abundance of tau and neurofilament epitopes in hippocampal neurofibrillary tangles.

Neurofibrillary tangles (NFTs) derive, in part, from normal neuronal cytoskeletal proteins, ie, large portions of tau (tau) but only restricted segments of the peripheral domains of the high- and middle-molecular weight neurofilament subunits. To learn more about the events leading to the incorporation of tau and neurofilament epitopes into NFTs, the relative abundance of tau and NF determinants in these lesions was quantitatively analyzed in hippocampi from Alzheimer disease (AD) patients and age-matched controls using monoclonal antibodies specific for tau or for NF proteins. Immunostained NFTs appeared qualitatively the same in both AD and controls, ie, every epitope found in AD NFTs occurred also in the NFTs of the control patients. However, in hippocampi with only a few tangles, tau epitopes, but no NF epitopes, were detected in NFTs. In contrast, both tau and NF epitopes were present in those tangles that were found in hippocampi with abundant NFTs. Nevertheless, the number of tau-positive NFTs generally exceeded the number of NF-positive NFTs. These findings indicate that tau epitopes are more abundant than NF epitopes in NFTs and that the formation of NFTs may be linked to a derangement in the normal metabolism of tau that is more extensive than alterations in NF protein metabolism.

Antibodies, Monoclonal↗
PubMed2003

Glial fibrillary tangles in diffuse neurofibrillary tangles with calcification.

In the present study the occurrence and distribution of glial fibrillary tangles (GFT) and their related structures in diffuse neurofibrillary tangles with calcification (DNTC) were investigated using Gallyas-Braak (GB) stain. Six cases neuropathologically diagnosed as DNTC were studied (two males and four females). The age at death ranged from 56 to 73 years, with an average of 63.5+/-7.5 years. GFT were classified morphologically, and their immunoreactivites for tau and ubiquitin were examined. Glial cells with GFT were identified with astrocytes and oligodendrocytes by immunostain for glial fibrillary acidic protein and transferrin, respectively. A small number of coiled bodies detected within the oligodendrocytes in the white matter of the cerebrum were positive for tau and ubiquitin. Cell clusters of thorn-shaped astrocytes were detected in the subcortical and subpial regions where gliosis occurred. Thorn-shaped astrocytes were positive for tau, but negative for ubiquitin. A small number of tuft-shaped astrocytes detected prominently in the temporal cortex and amygdala with numerous neurofibrillary tangles were positive for tau and ubiquitin. All three types of GFT were detected, especially in the temporal and limbic lobes, which were the most severely affected sites in DNTC. Moreover, various-shaped neurofibrillary tangles, aggregated rods and some argyrophilic threads were differentiated from GFT. They were positive for GB, but not detected within the glial cells.

Aged↗
PubMed1992

Evidence that neurofibrillary tangles undergo glial modification.

Ghost tangles, neurofibrillary tangles (NFTs) emerging into extracellular space, appear to be subjected to some microglial association in addition to an invasion of astrocytic processes. Our findings lead us to speculate that the NFTs undergo structural and immunocytochemical modification. Electron microscopic observation of the NFTs in the vascular region indicated either the discharge of NFTs into the vessel or formation of NFTs in the astrocytic end-foot.

Aged↗
PubMed2006

Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia.

Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3-4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.

Aged, 80 and over↗
PubMed2006

Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert.

Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3beta in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3beta; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3beta overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates.

Age Factors↗
PubMed1997

Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles.

Extracellular neurofibrillary tangles (eNFTs) are the insoluble cytoskeletal debris left behind when neurons with intracellular neurofibrillary tangles (iNFTs) die. Reactive microglia and reactive astrocytes gather around eNFTs. Many inflammatory proteins are deposited in their vicinity, including activated components of the classical complement pathway. Agents which are potential activators of the pathway include beta-amyloid protein (A beta) and amyloid P (AP), since these in vitro activators have been reported to be associated with both senile plaques (SPs) and eNFTs. To investigate the apparent order in which these proteins are deposited, we studied by immunohistochemistry the relative association of AP, A beta, and the classical complement protein C4d with eNFTs in Alzheimer's disease (AD), parkinsonism-dementia complex of Guam (lytico-bodig, LB), and elderly non-demented cases. In normal elderly cases with mild tangle development, most but not all eNFTs were AP positive. Substantially fewer eNFTs were C4d positive, and in two of the three cases no eNFTs were A beta positive. In AD and mild LB cases with more extensive tangle development, a high portion of eNFTs were AP positive, and most of them were C4d positive. Only a few were A beta positive. In severe LB cases, with dense tangle development, almost all eNFTs were AP and C4d positive, and a significant number were also A beta positive. AP seems to be deposited early in eNFT exposure and could therefore be a potential activator of the complement pathway, while A beta deposition occurs relatively late in the process, and is therefore unlikely to be responsible.

Aged↗
PubMed2002

Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation.

Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are two major histopathological lesions in Alzheimer's disease (AD). Although their aetiological relationship is unclear, both NFTs and dystrophic neurites of NPs display immunoreactivity for ubiquitin. This suggests that dysfunction in ubiquitin-mediated proteolysis and the resulting accumulation of ubiquitin-conjugated proteins may contribute to the origination of dystrophic neurites and NFTs. We recently discovered a novel constituent of neuropathological protein aggregates, ubiquitin-binding protein p62, with evidence that the accumulation of ubiquitin-conjugated proteins and p62 into cytoplasmic inclusions might be interconnected. In the present work we examined in detail the role of p62 in AD-type pathology, i.e. NFTs, NPs and neuropil threads. Using immunohistochemistry for p62, ubiquitin and hyperphosphorylated tau, we analysed parietal cortical samples of 15 clinicopathologically verified AD cases and nine nondemented aged subjects with abundant NPs. We found that p62 immunoreactivity appears early during neurofibrillary pathogenesis and is invariably and stably present in NFTs. In contrast, p62 was absent or barely detectable in neuropil threads. Furthermore, NP-associated dystrophic neurites were generally devoid of p62, regardless of their content of hyperphosphorylated tau and/or ubiquitin. The results suggest that early involvement of p62 might be critical in the aggregation of hyperphosphorylated tau into perikaryal aggregates, i.e. NFTs.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Neuron loss from the hippocampus of Alzheimer's disease exceeds extracellular neurofibrillary tangle formation.

Neurofibrillary tangle (NFT) formation in the CA1 region of the hippocampus is one of the early events in the pathogenesis of Alzheimer's disease (AD). As the disease progresses more NFTs form and there is substantial neuron loss. In this study we investigated whether NFT formation accounts for all the CA1 pyramidal neuron loss seen in AD. Using unbiased stereological techniques, we estimated the total number of neurons and the number of intra- and extra-cellular NFTs in the hippocampus of 10 patients with AD and 10 age-matched controls. Marked neuronal loss (approximately 60%) was identified in AD, although NFTs accounted for only a small proportion of this loss (2.2-17.2%, mean 8.1%). Analysis of NFT accumulation with duration of dementia showed a linear relationship, supporting the belief that NFTs progressively accumulate with time.

Alzheimer Disease↗
PubMed1981

Immunocytochemical studies of neurofibrillary tangles.

The molecular nature of neurofibrillary tangles of senile dementia of the Alzheimer type (SDAT) was studied by immunoperoxidase and immunofluorescence techniques. Five antiserums, including anti-humanbrain-2-cycle-purified-microtubule-fractions (2 x MT), anti-calf-brain-2 x MT, anti-sea-urchin-egg-tubulin, antibeef-brain-tubulin, and anti-human-brain-neurofilament(NF)-210-kilodalton(kd)-protein were tested for their binding to neurofibrillary tangles. The antihuman-2 x MT serum stained structures resembling neurofibrillary tangles, neurites of neuritic plaques, and microglialike cells in SDAT brains, but no such staining pattern was detected in normal brain sections. In neurons isolated from SDAT brains, about 40% of the tangles were labeled by the anti-human-2xMT serum with an identical pattern. Other antiserums tested did not preferentially bind tanglelike structures in tissue sections and bound to less than 5% of the tangles in isolated neurons. These results suggest that the antigenic sites of tubulin and NF proteins are not shared by neurofibrillary tangles. Different from the calf preparation, the human-2 x MT fractions contained a prominent protein band that was identical to ferritin in molecular weight and cross-reacted with anti-human-2 x MT and anti-human-ferritin serums. However, antiserums to this ferritinlike protein, or anti-ferritin, did not stain neurofibrillary tangles. Although neither the calf 2 x MT nor two other human MT fractions failed to elicit an antiserum that stained tangles, these fractions were able to remove the antihuman-2 x MT serum activity that binds to tangles. The data suggest that the protein (or proteins) that makes up neurofibrillary tangles of SDAT is present in various quantities in microtubule fractions of normal brain.

Alzheimer Disease↗
PubMed1991

Basic fibroblast growth factor binding is a marker for extracellular neurofibrillary tangles in Alzheimer disease.

Neurofibrillary tangles (NFT) are abnormal filamentous inclusions that develop in neurons in Alzheimer disease and other disorders. When neurons die, the neurofibrillary tangles that persist in the extracellular space show ultrastructural and antigenic changes. Both intra- and extracellular NFT have recently been shown to contain heparan sulfate proteoglycans (HSPGs). HSPGs are also present in other amyloid deposits in the brain and in systemic amyloidoses. Basic fibroblast growth factor (bFGF) is a heparin binding growth factor which is involved in angiogenesis and also has neurite promoting activity. We now report that bFGF binds avidly to extracellular NFT. Alz-50, a monoclonal antibody (MAb) to an abnormal form of tau and bFGF binding label mutually exclusive subpopulations of neurofibrillary tangles. bFGF binding is abolished by heparinase or heparitinase treatment and therefore is most likely based on the presence of HSPG. Binding of bFGF is a specific and sensitive morphological method to distinguish intra- from extracellular NFT. As intracellular NFT, which also contain HSPGs, are not labeled by bFGF binding, this finding also suggests that HSPGs are modified when the NFT become extracellular.

Aged↗