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Results for “Neurofibrillary Tangles”

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PubMed1997

Neuropathological changes in chronic adult hydrocephalus: cortical biopsies and autopsy findings.

BACKGROUND: The cortical changes resulting from chronic hydrocephalus in adults are not well defined. METHODS: Retrospective analysis of twenty-one patients (age 64-88 years) with a clinical diagnosis of "normal pressure hydrocephalus" who underwent cortical biopsy at the time of intracranial pressure monitoring or shunt insertion, and eight patients who were biopsied but not shunted. Eleven brains (age 26-92 years), seven from patients who could be considered to have "normal pressure hydrocephalus", were also examined following autopsy. Age- and sex-matched control brains with small ventricles and no history of dementia were compared to the hydrocephalic brains. Senile plaques and neurofibrillary tangles were assessed semiquantitatively and a non-parametric statistical analysis was employed. RESULTS: Five biopsies exhibited both senile plaques and rare neurofibrillary tangles, while two had only neurofibrillary tangles. Neurofibrillary tangles were more prevalent in hydrocephalic brains than in controls. There was no difference in the prevalence of senile plaques between the two groups. Grumose bodies in the substantia nigra were identified in five autopsy brains, a prevalence higher than in control brains. CONCLUSIONS: These pathological features are not specific for hydrocephalus; however, they suggest that long-standing ventriculomegaly is associated with degenerative brain changes in sites beyond the periventricular white matter. The presence of senile plaques in cortical biopsies from hydrocephalic patients does not appear to be a contraindication to shunting; however a prospective study in patients undergoing intracranial pressure monitoring would better address the issue.

Adult↗

PubMed1996

Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease.

A disturbance of the microtubule network in neurons containing neurofibrillary tangles (NFT), one of the characteristic neuropathological lesions in Alzheimer's disease, has been advocated as a central physiopathological mechanism leading to neuronal dysfunction in NFT-containing neurons. The accumulation of "paired helical filament-tau," the main proteineous component of NFT, in affected neurons has been proposed to induce a decrease of microtubule stability in these cells. To further explore the hypothesis of a decrease in microtubule stability in Alzheimer's disease, we have investigated in this study the relative content in stable microtubules in neurons with different amount of NFT. We used a double immunocytochemical labeling technique with antibodies to tau (as a marker of NFT) and to acetylated alpha-tubulin (as a marker of stable microtubules) and rated on a semi-quantitative scale the tau and acetylated alpha-tubulin-immunoreactivities in the same neurons. We observed a strong reduction in acetylated alpha-tubulin immunoreactivity in most NFT-bearing neurons; a statistical relationship between tau and acetylated alpha-tubulin immunoreactivity was demonstrated, assuming an inverse relationship between the presence of tau-immunoreactive NFT and tubulin-immunoreactivity in neurons. This reduction was already seen in the neuronal population with a relatively lower tau-immunoreactivity, suggesting that reduction in acetylated alpha-tubulin immunoreactivity, and reduction in microtubule stability, could be an early event in these cells.

Acetylation↗

PubMedDate not supplied

Neurofibrillary pathology--correlation with hippocampal formation atrophy in Alzheimer disease.

The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques and vessels. In AD, a similar severe volume loss was observed in both cellular layers and layers composed of fibers. A strong correlation between the decrease in the volume of hippocampal formation subdivisions and the decrease in the total number of neurons suggests a causative role for neuronal loss in hippocampal formation volumetric loss. Strong regional correlations between the relative decreases in the total number of neurons and the relative increases in the total number of neurofibrillary tangles implicates neurofibrillary pathology as a possible etiologic proximate factor in neuronal and volumetric loss in the hippocampal formation of AD patients.

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PubMed2001

Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons.

Human apolipoprotein (apo) E4, a major risk factor for Alzheimer's disease (AD), occurs in amyloid plaques and neurofibrillary tangles (NFTs) in AD brains; however, its role in the pathogenesis of these lesions is unclear. Here we demonstrate that carboxyl-terminal-truncated forms of apoE, which occur in AD brains and cultured neurons, induce intracellular NFT-like inclusions in neurons. These cytosolic inclusions were composed of phosphorylated tau, phosphorylated neurofilaments of high molecular weight, and truncated apoE. Truncated apoE4, especially apoE4(Delta 272--299), induced inclusions in up to 75% of transfected neuronal cells, but not in transfected nonneuronal cells. ApoE4 was more susceptible to truncation than apoE3 and resulted in much greater intracellular inclusion formation. These results suggest that apoE4 preferentially undergoes intracellular processing, creating a bioactive fragment that interacts with cytoskeletal components and induces NFT-like inclusions containing phosphorylated tau and phosphorylated neurofilaments of high molecular weight in neurons.

Aged↗

PubMedDate not supplied

Neurofibrillary tangle-associated alteration of stathmin in Alzheimer's disease.

Stathmin (p19), a 19-kDa cytosolic phosphorotein, plays a key role in converting extracellular signals into intracellular biochemical changes. Antibodies and cDNA specific for stathmin were used to study its levels and localization in normal and Alzheimer's disease (AD) brain tissue. The stathmin protein concentration was reduced in AD neocortex as assessed by Western blotting, whereas the concentration of its mRNA detected by both in situ hybridization and slot blot were increased in AD. The alteration of the stathmin protein concentration was negatively correlated with neurofibrillary tangle numbers but not with plaque numbers. Immunoreactivity was evenly localized to the cytoplasm of neurons in control cortical sections, whereas in AD it was preferentially localized to some of the neurofibrillary tangle-bearing neurons. Numbers of stathmin-positive neurons were inversely correlated with tangle numbers but not with plaque numbers in the frontal cortex of AD patients.

Alzheimer Disease↗

PubMedDate not supplied

Spatial, temporal and numeric analysis of Alzheimer changes in the nucleus coeruleus.

The distribution of neurofibrillary tangles in the nucleus coeruleus was topographically and quantitatively analyzed. The topographical analysis showed statistically significant differences with regard to the distribution of neurofibrillary tangles in the dorsal-ventral and medial-lateral axes. More neurofibrillary tangles were found to be located in the dorsal and medial regions than in ventral and lateral areas. No significant difference in neurofibrillary tangle content was found between the rostral and the caudal areas of the nucleus coeruleus. Neurofibrillary tangle formation begins in the central parts of the nucleus coeruleus. The total number of neuromelanized neurons in the nucleus coeruleus was determined using a modern, unbiased sampling scheme and related to the cortical stage of Alzheimer's disease-related neurofibrillary changes present. A statistically significant reduction (50%) in nucleus coeruleus neurons was evident only in cases meeting the histopathological criteria for Alzheimer's disease. The extent of reduction in the total number of neurons in the nucleus coeruleus did not correlate with the number of neurofibrillary tangles observed. Our data suggest that despite the relatively early susceptibility of the nucleus coeruleus to neurofibrillary tangle formation, significant neuronal loss appears to occur much later, with an estimated average delay time of at least 25 years. Nonetheless, comparison of the topographical pattern of neurofibrillary tangle formation and cell loss indicates that neuronal loss is tangle-related.

Age Factors↗

PubMed2001

Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons.

Neurofibrillary tangles are seen both in senile dementia of Alzheimer's disease and in juvenile dementia of Niemann-Pick type C disease. Apolipoprotein E is a main cholesterol transport molecule in brain. In Alzheimer's disease, possession of the apolipoprotein E epsilon4 allele is associated with an earlier onset in tangle formation and an increased tangle load. Niemann-Pick type C disease is a disorder with elevated intracellular levels of free cholesterol due to a genetic deficit in its transport. The link between tangle formation and cholesterol metabolism in both diseases suggests that alterations of intracellular free cholesterol levels could influence tangle formation. Using semiquantitative fluorescence microscopy with the free cholesterol probe filipin and analysing 939 neurons, we observed that mean levels of free cholesterol in tangle-bearing neurons were higher than those of adjacent tangle-free neurons.

Alzheimer Disease↗

PubMed2002

In vivo brain imaging of tangle burden in humans.

Cerebral neurofibrillary tangles (NFTs) accumulate in a predictable sequence decades before the clinical symptoms of Alzheimer's disease emerge, and the degree of tangle degeneration correlates with the severity of cognitive impairment. A valid in vivo marker of tangle burden, therefore, would be useful for presymptomatic and symptomatic disease detection and treatment monitoring. Recent advances using positron emission tomography (PET) indicate the feasibility of in vivo imaging that provides a combined signal of both neurofibrillary tangles and senile plaques. Such results are encouraging that a tangle-specific marker will be found; however, several methodological issues first need to be addressed, including scanner spatial resolution in the relatively small brain regions where tangles accumulate. NFT-specific imaging probes will need to be lipophilic in order to cross the blood-brain barrier and neuronal membranes and have a high binding affinity to NFTs with minimal nonspecific binding, which would result in a high signal-to-background ratio in PET images.

Alzheimer Disease↗

PubMed1999

Heparin injection into the adult rat hippocampus induces seizures in the absence of macroscopic abnormalities.

The pathological hallmarks of Alzheimer's disease include neurofibrillary tangles, neuropil threads and neuritic plaques. Neurofibrillary tangles and neuropil threads are comprised of paired helical filaments which are themselves composed of a hyperphosphorylated form of the microtubule-associated protein tau. Neuritic plaques are extracellular deposits of aggregated beta amyloid associated with neurites containing hyperphosphorylated tau. The mechanisms by which the neurofibrillary tangles and neuritic plaques develop in Alzhemier's disease are not clear but it is hypothesized that sulphated glycosaminoglycans are important in their formation. This impression is based on the finding that the glycosaminoglycan, heparan sulphate, is found associated with neurofibrillary tangles, neuritic plaques and neuropil threads while dermatan sulphate, chondroitin sulphate and keratan sulphate immunoreactivity is found around neuritic plaques in brains of Alzheimer's disease patients. Furthermore, in vitro studies demonstrate that sulphated glycosaminoglycans such as heparan sulphate and the closely related molecule heparin interact with tau and potentiate its phosphorylation by a number of serine/threonine kinases, reduce its ability to bind to microtubules and induce paired helical filament formation, all properties associated with tau isolated from Alzheimer's disease brain. Thus, we were interested to learn whether intracerebral injection of the sulphated glycosaminoglycan heparin would give rise to alterations in the cytoskeletal protein tau in the rat brain. Although no cytoskeletal changes were observed, to our considerable surprise we found that the intrahippocampal injection of heparin gave rise to seizures. We have investigated this unexpected effect further in vivo and by using in vitro electrophysiological techniques.

Animals↗

PubMed2000

Practical measures to simplify the Braak tangle staging method for routine pathological screening.

The examination of neurofibrillary tangles is now recommended for the diagnosis of Alzheimer's disease as their location and density can distinguish early, intermediate and late disease stages. While the Braak tangle staging protocol can identify these stages, it uses an uncommon silver stain and hippocampal sample. The present study evaluates the Braak protocol using commonly used methods and cases fulfilling either CERAD criteria for Alzheimer's disease, criteria for dementia with Lewy bodies or without neurological disease. Temporal and occipital cortices from 72 cases were stained using tau immunohistochemistry and the Gallyas and modified Bielschowsky silver stains. The modified Bielschowsky silver stain was equivalent to the Gallyas silver stain for tangle staging. Semiquantitative evaluation of neurofibrillary tangles in the hippocampus and the inferior temporal cortex provided equivalent information to that obtained using the original Braak tangle staging protocol (kappa statistic of 0.97). Comparison of this modification with the CERAD criteria provided moderate agreement (0.51) between diagnostic categories when cases with dementia with Lewy bodies were included, but substantially increased agreement (0.74) when they were excluded. This simplification of the Braak tangle staging protocol is easy to apply, can be readily incorporated into existing CERAD procedures, and helps to distinguish cases with neurofibrillary tangles from those with Lewy bodies.

Aged↗

PubMed2006

Neurofibrillary tangle-related synaptic alterations of spinal motor neurons of P301L tau transgenic mice.

We investigated axosomatic synapses of anterior horn cells of transgenic (TG) mice expressing mutant P301L human tau and non-transgenic (NTG) mice using electron microscopic methods to demonstrate the relationship between neurofibrillary tangles (NFTs) and synaptic alterations. Animals aged 3.5-8.5 months were used because at this age many motor neurons in TG mice have NFTs. We measured the perimeter of anterior horn cell perikarya, the number of boutons and total length of boutons in contact with the neuronal perikarya from the micrographs of NFT and non-NFT-bearing neurons. We also calculated the proportion of the perimeter covered by boutons, density of boutons and mean size of boutons. The density of synaptic boutons in contact with NFT-bearing neurons was significantly decreased compared to non-NFT-bearing neurons. These findings suggest that synaptic reduction occurs during neurofibrillary degeneration and is probably associated with NFT. In addition, synaptic boutons were detached from NFT-bearing neurons with the resulting space occupied by astrocytic processes, suggesting that astrocytes may be involved in the observed synaptic alterations.

Animals↗

PubMed1998

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

OBJECTIVE: To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. SETTING: Washington University Alzheimer's Disease Research Center, St Louis, Mo. DESIGN AND SUBJECTS: Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. MAIN OUTCOME MEASURES: Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. RESULTS: Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to epsilon4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. CONCLUSIONS: (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque-based neuropathologic criteria for AD are highly accurate.

Aged↗

PubMed1992

Glucose deprivation elicits neurofibrillary tangle-like antigenic changes in hippocampal neurons: prevention by NGF and bFGF.

A decrement in glucose utilization in brain was previously demonstrated in Alzheimer's disease (AD) and this abnormality has been proposed to play a role in the process of neuronal degeneration. We now report that glucose deprivation in cultured hippocampal neurons can result in antigenic alterations similar to those seen in AD neurofibrillary tangles (NFT) and, ultimately, cell death. Hypoglycemia caused an increase in neuronal immunoreactivity toward tau and ubiquitin antibodies. The antigenic alterations resulted from hypoglycemia-induced elevations in intracellular calcium levels as measured using the calcium indicator dye fura-2. The increased intraneuronal calcium levels, increased tau and ubiquitin immunoreactivities, and neuronal damage resulted from influx through the plasma membrane since they were not observed when cells were incubated in calcium-deficient medium. Neuronal damage and NFT-like antigenic changes were completely prevented by nerve growth factor (NGF) and basic fibroblast growth factor (bFGF), but not by epidermal growth factor (EGF). NGF and bFGF, but not EGF, prevented the aberrant rise in intracellular calcium levels that normally resulted from glucose deprivation. These data are consistent with the possibility that reduced glucose availability to neurons may contribute to the neuronal degeneration that occurs in AD. They also suggest that growth factors may normally protect neurons against hypoglycemic damage.

Animals↗

PubMed2001

A clinical and pathological study of motor neurone disease on Guam.

Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

Adult↗

PubMed1984

Imaging of calcium and aluminum in neurofibrillary tangle-bearing neurons in parkinsonism-dementia of Guam.

We report the distribution and imaging of calcium and aluminum in neurofibrillary tangle (NFT)-bearing neurons within Sommer's sector of the hippocampus in Guamanian patients with parkinsonism-dementia, using a method of computer-controlled electron beam x-ray micro-analysis and wavelength dispersive spectrometry. Calcium and aluminum were distributed in cell bodies and axonal processes of NFT-bearing neurons. The elemental images show that both calcium and aluminum deposits occur within the same NFT-bearing hippocampal neuron in this dementing disease, suggesting that these elements are involved in NFT formation. No prominent concentrations of calcium and aluminum were imaged in non-NFT-containing regions within the pyramidal cell layer of the parkinsonism-dementia cases or in the control cases. These findings support the hypothesis that secondary hyperparathyroidism resulting from low environmental calcium and magnesium in the high-incidence focus of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam had led to abnormal deposition of calcium and aluminum in the central nervous system.

Aged↗

PubMed2000

Cdk5 and munc-18/p67 co-localization in early stage neurofibrillary tangles-bearing neurons in Alzheimer type dementia brains.

Hyperphosphorylation of tau protein occurs during the formation of paired helical filament (PHF) in the brain with Alzheimer's disease. As previously reported, cyclin-dependent kinase (cdk) 5 can phosphorylate tau at the site of abnormally phosphorylated in PHF. To characterize the relationship between cdk5 and PHF-tau, we investigated the localization of cdk5 and its regulator, p67 (munc 18), in the hippocampus and temporal lobes from 12 Alzheimer type dementia (ATD) patients and 5 controls using immunohistochemical procedures. The specificity of antibodies was confirmed with Western blot analysis. Anti-cdk5 antibody diffusely stained the perikarya of some tau2-positive or neurofibrillary tangle (NFT)-bearing neurons in ATD brains, while cdk5-positive staining was scarcely found in control brains. Anti-p67 antibody also showed stronger immunoreactivity of pyramidal neurons in ATD brains than in control brains. Double immunostaining with anti-cdk5 and anti-p67 antibodies revealed co-localization of both molecules in some pyramidal neurons. These findings suggest that cdk5 is activated by p67 at the early stage of NFT formation and accelerates NFT formation. In cdk5-positive and p67-negative neurons, cdk5 may be activated by other regulator molecules such as p35. In addition, cdk5-positive reactive astrocytes were found close to cdk5-positive NFT-bearing neurons m ATD brains but not in control brains, suggesting a correlation between NFT and reactive astrocytes.

Aged↗

PubMed2002

Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease.

Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). We show here that the pattern of tau phosphorylation correlates with the loss of neuronal integrity. Studies using 11 phosphorylation dependent tau antibodies and a panel of AD cases of varying severity were evaluated in terms of three stages of neurofibrillary tangle development: (1) pre-neurofibrillary tangle, (2) intra-, and (3) extra-neuronal neurofibrillary tangles. The pretangle state, in which neurons display nonfibrillar, punctate regions in the cytoplasm, sound dendrites, somas, and nuclei, was observed especially with phospho-tau antibodies TG3 (pT231), pS262, and pT153. Intraneuronal neurofibrillary tangles are homogenously stained with fibrillar tau structures, which were most prominently stained with pT175/181, 12E8 (pS262/pS356), pS422, pS46, pS214 antibodies. Extracellular NFTs, which contain substantial filamentous tau, are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intracellular NFT. The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations.

Aged↗

PubMed2006

Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer's disease and healthy subjects.

While the presence of naturally occurring antibodies (Abs) against amyloid-beta in AD patients and healthy subjects have been repeatedly reported, no data on the presence of naturally occurring Abs against tau protein, in its unphosphorylated as well as its pathologically phosphorylated state, has been reported so far. We describe here the detection of circulating Abs against unphosphorylated and pathologically phosphorylated tau protein in sera of 17 aged subjects: nine Alzheimer's disease (AD) patients and eight healthy individuals. An ongoing autoimmune process may take place, as is suggested by the presence of both IgM class anti-tau Abs, as well as IgG. A preliminary evidence for higher anti-phosphorylated-tau Abs of IgM class in AD patients relative to controls is indicated, but demands further confirmation in a larger sample. Detection of naturally occurring anti-tau antibodies may point to the possibility that some autoimmune process may take place against the tau neuronal protein, including its pathologically phosphorylated state which compose the neurofibrillary tangles. Whether these Abs are neuroprotective or neurotoxic - is unknown, as it is with anti-amyloid-beta Abs.

Aged↗