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PubMed1988

Intraneuronal and extracellular neurofibrillary tangles exhibit mutually exclusive cytoskeletal antigens.

We examined the possibility that neurofibrillary tangles (NFTs) were heterogeneous in postmortem hippocampus from 22 patients with or without senile dementia of the Alzheimer type. Intraneuronal NFTs and extracellular, or "ghost," NFTs were recognized in situ by only one or the other of two monoclonal antibodies. The first monoclonal antibody, RMO87, stained only intraneuronal NFTs and is specific for phosphate-dependent epitopes in tau and the two high molecular weight neurofilament proteins. The second monoclonal antibody, 2.2B10, is specific for glial fibrillary acidic protein, and it stained only the RMO87-negative extracellular NFTs. Treatment of sections with alkaline phosphatase or sodium dodecyl sulfate, and the isolation of NFTs from hippocampus, did not expose RMO87 binding sites in extracellular NFTs. These observations indicate that neurofilament-like and tau-like epitopes can be lost from NFTs in situ, and that at least two populations of morphologically and immunochemically distinct NFTs exist.

Aged↗
PubMed1985

Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study.

The reactivity of neurofibrillary tangles (NFT) of Alzheimer's disease with several antisera has been studied by immunocytochemistry. They were heavily labelled by an antiserum prepared against isolated NFT; the latter also remained stainable by Bodian-silver method. Some NFT were labelled on vibratome sections by an antimicrotubular protein but remained able to be counterstained by Congo Red, suggesting this labelling could demonstrate material trapped in NFT. The immunoelectron labelling shows that the abnormal filaments, straight as well as 'twisted', are the only structures recognised by the anti-NFT serum. This labelling was prevented only by pre-incubation with fractions enriched in NFT, confirming the presence of unique antigenic determinants in the latter.

Alzheimer Disease↗
PubMed1991

Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease.

Alzheimer's disease is characterized by the presence of abundant neurofibrillary tangles and beta-amyloid deposits in neocortex, hippocampus and amygdala. The major protein components of tangles and plaques have recently been identified. These findings, briefly reviewed here, will allow researchers to design investigations that will lead to an understanding of the pathogenesis of the disease and to the development of new therapeutic approaches that may result in an effective treatment.

Alzheimer Disease↗
PubMed2000

Neurofibrillary tangles in progressive supranuclear palsy brains exhibit immunoreactivity to frameshift mutant ubiquitin-B protein.

In Alzheimer's disease (AD) neurofibrillary tangles (NFT) are strongly tau and ubiquitin immunopositive, and contain an aberrant form of ubiquitin derived from the ubiquitin-B gene denoted as UBB+1. We explored whether the tau-related NFT seen in another neurodegenerative disease, progressive supranuclear palsy (PSP), also showed an accumulation of UBB+1. Three cases of PSP were examined immunohistochemically for tau protein, ubiquitin-protein conjugates and UBB+1 using single and double labelling. We conclude that UBB+1 is associated with compact globose tangles rather than dispersed accumulations of tau in PSP, showing that its presence is not unique to AD. We propose that aggregation of ubiquitinated proteins into compact inclusions in PSP might be due to inhibition of the degradation of multiubiquitinated proteins by ubiquitin chains containing proximal UBB+1 rather than normal ubiquitin.

Aged↗
PubMed1994

Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects.

In a consecutive autopsy series of 580 demented elderly subjects, 256 with the clinical diagnosis of probable/possible Alzheimer's disease (AD), there were 10 cases aged between 80 and 99 years with moderate to severe dementia or confusional state in which neuropathological studies revealed abundant neurofibrillary tangles with predominant involvement of the allocortex (entorhinal region, subiculum, CA 1 sector of hippocampus, amygdala) but no or only very few senile plaques. Small numbers of diffuse deposits of beta A4 amyloid protein were present in the entorhinal cortex of 3 and in the isocortex of 5 brains, while neuritic plaques were totally absent. Only a few cases of this "senile dementia with tangles only" or, more correctly, "neurofibrillary predominant type of AD" corresponding to the limbic stage of neuritic AD pathology have been described in the literature. This rare subtype occurring in very old (over 80 years of age) subjects that does not fall within the currently used neuropathological criteria for diagnosis of AD warrants further clinico-pathological documentation.

Aged↗
PubMed1997

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Age of Onset↗
PubMed2003

Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice.

Transgenic mice expressing human tau with P301L missense mutation (JNPL3) develop progressive amyotrophy, neurofibrillary degeneration, and neuronal loss. Mating of JNPL3 with transgenic mice expressing mutant amyloid precursor protein (Tg2576) leads to bigenic (TAPP) mice with enhanced neurofibrillary pathology. TAPP and JNPL3 mice were studied with immunocytochemistry and immunoblotting with antibodies to glycogen synthase kinase-3 (GKS3) to determine whether the development of tauopathy is associated with activation or increased expression of GSK3, and when the observed changes occur with respect to neurofibrillary tangle (NFT) formation. Accumulation of GSK3alpha/beta phosphorylated at Y279/216 was observed in neurons containing NFTs and granulovacuolar degeneration (GVD), but not in normal neurons or neurons with pretangles. More GSK3 immunoreactive NFTs were detected in TAPP than JNPL3 mice, especially in the amygdala. These differences were notable only in old animals. There was no significant difference between animals with and without NFTs in the level of total, inactive, or Y216-phosphorylated (pY216)GSK3beta. No apparent GSK3 accumulation was detected in neurons in Tg2576 mice. There was also no significant difference in the distribution of GSK3 in lysates fractionated based on their solubility in various reagents, including the sarkosyl-insoluble fraction. The results suggest that the pY216 GSK3beta accumulates in NFT and GVD due to redistribution rather than increased expression or activation, and that pre-existence of tau abnormalities is required for APP/Abeta to exert their effects on tau pathology in TAPP mice.

Animals↗
PubMed1988

Neurofibrillary tangles in cholinergic pedunculopontine neurons in Alzheimer's disease.

The cholinergic neurons located within the pedunculopontine nucleus (Ch5) of patients with Alzheimer's disease (AD; n = 15), Parkinson's disease (PD; n = 2), and neurologically normal (n = 6) subjects were visualized immunohistochemically using choline acetyltransferase, pharmacohistochemically using acetylcholinesterase, or by reduced histochemical methods using nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Each histochemical procedure localized a well-delineated, compact lateral group and a more diffuse medial group of neurons within the pedunculopontine nucleus. Co-localization experiments revealed that all three enzymes marked the same population of cholinergic neurons. The extent of pathological alterations associated with the cholinergic neurons within the compact lateral sector of the pedunculopontine nucleus was examined in sections that reacted for NADPH-d, counterstained with thioflavin-S. The average number of neurofibrillary tangles within this portion of the pedunculopontine nucleus was 25.4 (range 0-70) in patients with AD, 1.5 (range 1-2) in those with PD, and 1.2 (range 0-4) in aged control subjects. Of the total number of neurofibrillary tangles counted in AD cases, 72.7% were end-stage ghosts and 27.3% were tangle-bearing neurons. The pathological alteration of cholinergic neurons of the compact lateral aspect of the pedunculopontine nucleus may play a role in some of the behavioral features characteristic of AD.

Acetylcholinesterase↗
PubMed1996

Synaptic pathology in Alzheimer's disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele.

Alzheimer's disease (AD) is characterised by an increased number of senile plaques (SP) and neurofibrillary tangles (NFT) as compared with that found in non-demented individuals of the same age, and a marked degeneration and loss of synapses. One of the main risk-factors for the disorder is inheritance of the apolipoprotein E4 (ApoE4) allele. To further study the relation between these pathogenetic substrates for AD, we quantified the synaptic vesicle membrane protein rab3a in brain tissue from 19 patients with AD and 9 age-matched control subjects. Rab3a levels were reduced in AD, both in the hippocampus (60% of control level, p < 0.0001), and in the frontal cortex (68% of control level, p < 0.01), but not in the cerebellum (92% of control level). Within the AD group, lower rab3a levels were found both with increasing duration and severity of dementia. These findings further support that synaptic pathology is closely correlated to the clinical dementia in AD. In contrast, no significant correlations were found between SP counts and duration or severity of dementia, while higher NFT counts in the frontal cortex were found with increasing severity of dementia (r = 0.54, p < 0.05). There were no significant correlations between the rab3a level and SP or NFT counts, and by immunohistochemistry, reduced rab3a immunostaining was found throughout the neuropil in AD brain, without relation to SP or NFT. These findings suggest that the synaptic pathology in AD is not closely related to the presence of SP and NFT. No significant differences in rab3a levels were found in any brain region between AD patients possessing different numbers of the ApoE4 allele, suggesting that, although ApoE4 is A risk factor for earlier development of AD, the degree of synaptic pathology does not differ between patients with or without the ApoE4 allele.

Aged↗
PubMed1993

[The aging of central nervous system in methylmercury intoxication in Niigata, Japan--quantitative investigation of neurofibrillary tangles and senile plaques].

In order to elucidate the progression of aging process in the brains of methylmercury intoxication in humans, neurofibrillary tangles (NFT) and senile plaques (SP) were examined quantitatively in the temporal lobe and calcarine cortex of 16 patients with methylmercury intoxication and 12 control subjects by using tau and beta-peptide immunostained preparations. The numbers of NFT and SP in the patients of methylmercury intoxication were almost equal to those in control subjects, and statistically there is no significant difference. The findings indicate that the methylmercury intoxication in humans does not induce or exacerbate the NFT or SP forming disease process at least in these regions in the brain.

Aged↗
PubMed1993

Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer's disease.

We studied the number of large-sized neurons and neurofibrillary tangles (NFT) in the tuberomammillary nucleus (TM) of the hypothalamus from cases with Alzheimer's disease (AD) and age-matched controls. Numerous NFT were found in TM of AD. However, NFT was never observed in this nucleus of age-matched controls. The number of large-sized neurons was significantly reduced in AD compared with that in controls. Since the majority of large neurons in TM appear to correspond to histamine neurons, the loss of large neurons observed in TM may, at least partly, cause the histaminergic dysfunction in AD brain.

Aged↗
PubMed2002

Beta-amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome.

Individuals with Down syndrome (DS) and Alzheimer's disease (AD) develop senile plaques, neurofibrillary tangles (NFT), and neuron loss. Recent studies demonstrate the activation of apoptotic pathways in AD; less data is available in DS. The DS brain was examined using immunocytochemistry and antibodies against the active fragment of caspase-8 (AC, 8) and to caspase-3 cleavage products of fodrin (CCP), a neuronal cytoskeleton protein. The hippocampus demonstrated widespread accumulation of fodrin CCP and AC8 in NFTs and dystrophic neurites. Individual neurons contained intracellular beta-amyloid (Abeta) and fodrin CCP providing evidence that caspase activation can occur with both NFT and Abeta. Abeta within or around neurons in addition to contributing to NFT formation may also trigger apoptotic pathways. Caspase activation may lead to the cleavage of critical cellular proteins and neuronal cell death associated with DS.

Adult↗
PubMed1995

Aluminium detected in senile plaques and neurofibrillary tangles is contained in lipofuscin granules with silicon, probably as aluminosilicate.

Aluminium and silicon are incidentally found in senile plaques (SP) and neurofibrillary tangles (NFT) of brains with Alzheimer's disease (AD), and have been considered as one of the risk factors for senile dementia. Since lipofuscin granules were concentrated concomitantly with SP and NFT in the high density fraction in subcellular fractionation of autopsied brains and are solid in nature, it was suspected that aluminum and silicon are accumulated in lipofuscin granules. Therefore, elemental analyses of partially purified lipofuscin granules from autopsied brains with AD and those without dementia, were attempted by energy dispersive X-ray spectrometry with a scanning electron microscope. It was demonstrated by a mapping method that aluminum and silicon were accumulated in some lipofuscin granules, probably as aluminosilicate. In addition, it was demonstrated by fluorescence microscopy of Bodian stained paraffin sections, that many SP and NFT contained lipofuscin granules, although lipofuscin granules were not always specific to those neuropathological changes. These results imply that aluminum detected in SP and NFT is due to lipofuscin granules and can explain the cause of discrepancies in the reports on the presence of aluminum in SP and NFT.

Aged↗
PubMed1993

Is the clustering of neurofibrillary tangles in Alzheimer's patients related to the cells of origin of specific cortico-cortical projections?

The spatial pattern of cellular neurofibrillary tangles (NFT) was studied in the supra- and infragranular layers of various cortical regions in cases of Alzheimer's disease (AD). The objective was to test the hypothesis that NFT formation was associated with the cells of origin of specific cortico-cortical projections. The novel feature of the study was that pattern analysis enabled the dimension and spacing of NFT clusters along the cortical ribbon to be estimated. In the majority of brain regions studied, NFT occurred in clusters of neurons which were regularly spaced along the cortical strip. This pattern is consistent with the predicted distribution of the cells of origin of specific cortico-cortico projections. Mean NFT cluster size varied from 250 to > 12800 microns in different cortical tissues suggesting either variation in the size of the cell clusters or a dynamic process in the development of NFT in relation to these cell clusters. The formation of NFT in cell clusters which may give rise to the feed-forward and feed-back cortico-cortical projections suggests a possible route of spread of NFT pathology in AD between cortical regions and from the cortex to subcortical areas.

Alzheimer Disease↗
PubMed2005

Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein.

We performed proteomic analysis of neurofibrillary tangles (NFTs) obtained by laser capture microdissection from pyramidal neurons in hippocampal sector CA1 in patients with Alzheimer disease (AD) using liquid chromatography (LC)-mass spectrometry (MS)/MS. We discovered a total of 155 proteins in laser captured NFT's, 72 of which were identified by multiple unique peptides. Of these 72 proteins, 63 had previously unknown association with NFTs; one of these was glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We validated by immunohistochemistry that GAPDH co-localized with the majority of NFTs as well as plaque-like structures in AD brain and was co-immunoprecipitated by antibodies to abnormal forms of tau in AD, but not tau from AD temporal cortex. Characterization of GAPDH showed that it, along with phosphorylated tau and Abeta peptides, was present in detergent-insoluble fractions from AD temporal cortex but not from age-matched controls. These data are the first proteomic investigation of NFTs. Moreover, our results validate this approach by demonstrating that GAPDH, a glycolytic and microtubule binding protein, not only co-localized to NFTs and immunoprecipitated with PHF-tau, but also is one of the few proteins known to undergo conversion to a detergent-insoluble form in AD.

Alzheimer Disease↗
PubMed2006

Activated c-Jun is present in neurofibrillary tangles in Alzheimer's disease brains.

Alzheimer's disease (AD) pathology is characterized by the presence of insoluble beta-amyoid deposits and neurofibrillary tangles containing hyperphosphorylated tau. Increased expression of the immediate early gene product c-Jun has also been reported in post-mortem AD brains, and the presence of upstream regulators of c-Jun has been described in tangle formations. Here, we report the presence of c-Jun specifically phosphorylated on ser-63, but not ser-73, in tangle-bearing neurons and in 'late-stage' extracellular tangles in AD brains. Western blot analysis confirmed the presence of c-Jun phosphorylated on ser-63 but not on ser-73 in AD brain tissue. The expression of differentially phosphorylated c-Jun in the AD brain may reflect the contradictory roles of these phosphorylation sites in neurons. Furthermore, the inappropriate sequestration of phosphorylated c-Jun in tangles in AD brains may contribute to AD pathology and neurodegeneration.

Aged↗
PubMed1998

Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain.

The formation of neurofibrillary tangles in Alzheimer's disease shows a preferential involvement of certain cytoarchitecturally defined cortical areas suggesting systematic differences in regional neuronal vulnerability. The cellular and molecular nature of this selective neuronal vulnerability that follows a certain hierarchy of structural brain organization is largely unknown. In the present study, we compared the regional pattern of tangle density in Alzheimer's disease with systematic regional differences in neuronal plasticity that can be observed both during ageing and in Alzheimer's disease. Changes in dendritic length and arborization of Golgi-impregnated pyramidal neurons were analysed after three-dimensional reconstruction in 12 cortical areas. The intensity of dendritic remodelling that was observed during ageing as well as in Alzheimer's disease was regionally different and decreased in the following order: transentorhinal region > limbic areas (entorhinal region, hippocampus) > non-primary association areas (37, 40, 46) > primary sensory association areas (7, 18, 22) > primary sensory and motor cortex (17, 41, 4). These regional differences of neuronal plasticity follow the same pattern as the regional vulnerability to tangle formation in Alzheimer's disease. The results of the present study provide evidence that a high degree of structural neuronal plasticity might predispose neurons to tangle formation.

Adult↗
PubMed1991

Severity of dementia in Alzheimer disease and neurofibrillary tangles in multiple brain regions.

We studied the relationship of numbers of neurofibrillary tangles (NFTs) in selected cortical and subcortical sites to the duration of clinical disease and severity of dementia. Sixteen patients with a clinical diagnosis of "probable" Alzheimer disease were screened with standardized neuropsychological instruments to estimate the severity of dementia. Tissues were obtained at autopsy from the subiculum, four neocortical areas, and the nucleus basalis of Meynert: NFT counts were assessed with the thioflavin S stain. Overall, the subiculum showed the most NFTs, followed by visual association and premotor cortices, primary cortex (motor and visual), and the nucleus basalis. NFT counts were significantly positively correlated with the duration of disease in the nucleus basalis and less strongly in the motor cortex. Neuropsychological impairment was significantly correlated with NFT counts only in the nucleus basalis. In turn, counts in the nucleus basalis were reliably correlated with those in all other brain regions except the subiculum. Counts in the subiculum showed no correlation with any other area. Numbers of NFTs within functionally related sites, the primary motor and premotor cortices or primary and visual association cortices, were significantly or near-significantly correlated, whereas motor and visual cortical counts showed no intercorrelation. Our results indicate that although there is less NFT accumulation in the nucleus basalis than in many other brain regions, counts in this structure bear a close relationship to disease severity and duration and to NFT accumulation in other regions.

Aged↗