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Results for “Neurofibrillary Tangles”

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PubMed2001

Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles.

The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster. Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.

Acetylcholine↗

PubMed1993

A topographical study of senile plaques and neurofibrillary tangles in the hippocampi of patients with Alzheimer's disease and cognitively impaired patients with schizophrenia.

Neuropsychological testing of elderly schizophrenic patients reveals that a significant portion of this population exhibit varying degrees of cognitive impairment. Since Alzheimer's disease is the most common cause of dementia in geriatric patients, we investigated whether the cognitive decline observed in schizophrenia is the result of degenerative changes analogous to those characteristic of Alzheimer's disease. For this purpose, the number and distribution of senile plaques and neurofibrillary tangles were mapped in the hippocampi of 10 cognitively impaired schizophrenic patients, 10 patients with Alzheimer's disease, and 10 patients with dementia not attributed to either schizophrenia or Alzheimer's disease. In Alzheimer's disease, degenerative changes invariably predominated in the CA1 subfield, subiculum, and proisocortex. By contrast, findings characteristic of Alzheimer's disease were virtually never observed in the hippocampi of schizophrenic and other cognitively impaired patients. In some patients with Alzheimer's disease, the presence of senile plaques in the molecular layer of the dentate gyrus suggested the existence of an underlying entorhinal cortex lesion. Similar dentate gyrus pathology was never found in any of the other patients. The authors conclude that cognitive impairment in schizophrenia is not the result of degenerative changes analogous to those found in Alzheimer's disease.

Aged↗

PubMedDate not supplied

Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study.

Midlife hypertension is associated with later development of cognitive impairment, vascular dementia (VsD), and possibly Alzheimer's disease (AD). Neuropathic cerebrovascular lesions and brain atrophy have been associated with elevated blood pressure (BP), however, to our knowledge there have been no prospective investigations of an association of blood pressure levels measured in midlife with the microscopic lesions of AD. We investigated the relationship of BP level in midlife to development of neurofibrillary tangles (NFT), neuritic plaques (NP), and low brain weight at autopsy among Japanese-American men who were members of the Honolulu Heart Program/Honolulu-Asia aging Study (HHP/HAAS) cohort. The HHP/HAAS is a population-based, longitudinal study of cognitive function and dementia with 36 years of follow-up. Neocortical and hippocampal NFT and NP were counted per mm(2), and fixed brain weight was measured for 243 decedents. Elevated systolic BP, (> or =160 mm Hg) in midlife was associated with low brain weight and greater numbers of NP in both neocortex and hippocampus. Diastolic BP elevation, (> or =95 mm Hg) was associated with greater numbers of NFT in hippocampus. Results indicate that in addition to the accepted association of high BP with neuropathic cerebrovascular lesions, there is a direct relationship with brain atrophy, NP and NFT.

Aged↗

PubMed2003

Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density.

Intracellular accumulation of PHFtau in Alzheimer's disease (AD) disrupts the neuronal cytoskeleton and other neuronal machinery and contributes to axonal and dendritic degeneration, and neuronal death. Furthermore, amyloid-beta (Abeta) has been reported to be toxic to neurons and neurites. While loss of presynaptic elements is an established feature of AD, the nature and extent of dendritic degeneration has been infrequently studied. We investigated MAP2-immunoreactive dendrites using a novel method of high-throughput quantification and also measured cortical thickness and the densities of NeuN-immunoreactive neurons, PHFtau neurofibrillary tangles (NFTs), and Abeta plaque burden in the subiculum in AD and elderly controls. Corrected for atrophy, the "dendritic arborization index" was significantly reduced by up to 66% in all three layers of the subiculum. Laminar thickness was reduced by an average 33% and there was a marked reduction in neuron density of approximately 50%. As expected, NFTs and Abeta plaques were significantly increased in AD. Dendritic arborization indices negatively correlated with NFT densities while no significant correlations were found with Abeta plaque densities. The pattern of dendritic loss in the subiculum and the correlations with NFT densities respectively suggest that deafferentation and intrinsic neurofibrillary degeneration both may contribute to dendritic loss in AD.

Aged↗

PubMed2006

Increased neurofibrillary tangles in the brains of older pedestrians killed in traffic accidents.

BACKGROUND/AIMS: Older people are over-represented in pedestrian fatalities, and it has been suggested that the presence of cognitive impairment or dementia in these individuals may contribute to their accidents. Using neuropathological methods, we aimed to compare the prevalence of dementia pathology in fatally injured older pedestrians with similarly aged ambulatory subjects who died from other causes. METHODS: The brains of 52 pedestrians (65-93 years) and 52 controls (65-92 years) were assessed for neurofibrillary tangles (NFT), neuritic plaques, Lewy bodies and vascular lesions using established neuropathological criteria. RESULTS: The examination for Alzheimer's disease (AD) pathology showed that 43% of the pedestrians had NFT scores of III-VI using Braak and Braak staging, compared with 23% of the controls (p < 0.05, Fisher's exact test), indicating incipient, possible or probable AD. There were no differences in the prevalence of pathology for vascular dementia or dementia with Lewy bodies. CONCLUSION: These results suggest that cognitive decline associated with AD, even in the earliest stages of the disease, may be a factor in fatal traffic accidents for older pedestrians. Special measures for pedestrian safety are necessary in areas with high densities of older citizens and especially for those diagnosed as having a mild cognitive impairment or AD.

Accidents, Traffic↗

PubMed1999

Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangles, and senile plaques.

Inducible nitric oxide synthase (iNOS) is involved in the generation of nitric oxide, a molecule with multiple biological activities. Although iNOS expression may be part of antimicrobial armamentarium, inappropriate expression of iNOS can potentially lead to damage to the host. In this report, we determined the expression of iNOS by immunocytochemistry in the hippocampus of the Alzheimer brains (AD) as well as in young and old normal brains. The results showed localization of iNOS immunoreactivity to Hirano bodies of the AD hippocampus. In addition, small granular iNOS immunoreactive profiles were detected associated with senile plaques and extracellular neurofibrillary tangles. In the hippocampus of control brains, morphologically similar profiles were immunoreactive for iNOS, but in far fewer numbers than in AD hippocampus. The results suggest that iNOS is expressed in a subset of pyramidal neurons in the AD hippocampus, and that iNOS may be involved in the pathogenesis of neuronal degeneration in AD.

Adult↗

PubMed1991

Extracellular neurofibrillary tangles associated with degenerating neurites and neuropil threads in Alzheimer-type dementia.

We examined the cellular components of extracellular neurofibrillary tangles (E-NFT) in the hippocampal areas in cases with Alzheimer-type dementia. Immunohistochemically, the E-NFT were labeled for the C terminus of tau and glial fibrillary acidic protein. Moreover, the majority of the E-NFT was associated with intensely argyrophilic rods and with tau- and ubiquitin-immunoreactive dots. Ultrastructurally, the E-NFT consisted mainly of extracellular paired helical filaments (PHF) and astroglial processes. The extracellular PHF tended to be straighter and thinner. One third of the E-NFT was associated with small degenerating neurites containing many dense bodies and with neuropil threads containing PHF. These findings suggested that extracellular PHF promote both intense astroglial reaction and neuritic alteration, and that the E-NFT are continuously changing their morphology.

Aged↗

PubMed2002

A case of diffuse neurofibrillary tangles with calcification.

We report a 79-year-old female with atypical senile dementia with Fahr-type calcification. The patient started to show memory disturbance at the age of 75 years, followed by visual hallucination, stereotypy, personality changes such as irritability, aggression and disinhibition. Brain computed tomography (CT) demonstrated bilateral and symmetric calcification of the basal ganglia and thalamus. Magnetic resonance imaging (MRI) revealed diffuse cortical atrophy pronounced in the fronto-temporal areas. On MRI T1-weighted images the calcified areas showed a mixture of low- and high-intensity signals. Based on the overlapping clinical symptoms of Alzheimer's disease and Pick's disease, together with the brain CT and MRI findings, we clinically diagnosed the patient as having 'diffuse neurofibrillary tangles with calcification' (DNTC). The characteristics of psychiatric symptoms and neuroradiological findings in DNTC are discussed.

Aged↗

PubMedDate not supplied

Universal isolation of cross-linked peptides: application to neurofibrillary tangles.

A universal procedure to isolate cross-linked peptides has been demonstrated. The procedure relies on initially converting the epsilon-amino groups of lysine to dimethyl lysine by reductive methylation with sodium cyanoborohydride and formaldehyde. The lysine-modified protein is proteolytically cleaved and the resulting alpha-amino groups derivatized with methoxypoly(ethylene glycol)5000 succinyl hydroxysuccinimide. Any unintentional derivatization of tyrosine side chains can be reversed by incubation under mildly alkaline conditions. The cross-linked polypeptides contain two poly(ethylene glycol)5000 chains while non-cross-linked peptides contain a single poly(ethylene glycol)5000 chain. The two populations of peptides can be separated by gel filtration chromatography. This procedure has been shown capable of isolating cross-linked peptides using glutathione, lysozyme, chemically cross-linked hemoglobin, and neurofibrillary tangles isolated from the brain of a case of Alzheimer's disease.

Alzheimer Disease↗

PubMed1998

Both N-terminal and C-terminal fragments of presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease.

Presenilin 1 (PS1) is a causative gene for chromosome 14-linked familial Alzheimer's disease. The gene product is known to be cleaved into N-terminal fragments (PS1-N) and C-terminal fragments (PS1-C). To understand the pathophysiological role of PS1, we conducted immunohistochemical studies using antibodies specific for PS1-N and PS1-C in sporadic Alzheimer's disease (AD). Both antibodies showed punctuate staining exclusively in neurons and their processes in both control and AD brains. PS1-N immunolabeling colocalized with neurofibrillary tangles (NFTs) in 36% of NFT-bearing neurons and with dystrophic neurites in 28% of senile plaques (SPs). PS1-C immunolabeling colocalized with dystrophic neurites in 70% of NFT-bearing SPs and with intraneuronal NFTs in 32% of NFT-bearing neurons. Both antibodies did not detect PHF-tau-positive neuropil threads and Abeta amyloid fibrils. The colocalization was also found in 33-38 % of NFT-bearing neurons in progressive supranuclear palsy. These results indicate that both PS1-N and PS1-C fragments are deposited in part of NFT-bearing neurons and dystrophic neurites in SPs; both are the pathologic hallmarks of AD.

Alzheimer Disease↗

PubMed1998

Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies.

We report four patients with a new type of familial parkinsonism and dementia consisting of an autosomal dominant inheritance, dopa-responsive parkinsonism, severe dementia, variable myoclonus and autonomic disturbances. Autopsy of two patients revealed symmetrical cerebral atrophy with fronto-temporal dominant distribution, and marked depigmentation in the substantia nigra and locus ceruleus. Neuronal loss and gliosis were observed in the deep cerebral cortex and amygdala as well as in the areas vulnerable to Parkinson's disease. In the cerebral cortex, swollen neurons with frequent granulovacuolar changes were observed, consisting of ballooned neurons and those with argyrophilic intracytoplasmic inclusions, in addition to neuropil threads. Atypical neurofibrillary tangles, which barely stained with tau antibodies, were numerous in the upper cortical layers, consisting of 15-nm straight tubules. In addition, tau-negative astrocytic fibrillary tangles were also frequent. Electron microscopically, the ballooned neurons and argyrophilic neuronal inclusions contained filamentous structures coated with fuzzy electron-dense deposits. The inclusions showed immunohistochemical features different from those of cortical Lewy bodies and Pick bodies. Occasional Lewy bodies were present in the brain stem lesions of both patients. In two of our patients, the pathology in the brain stem was similar to that of Parkinson's disease, whereas their cerebral pathology was unusual and has not been reported previously.

Adult↗

PubMed1994

Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer beta-amyloid deposition.

The localization of apolipoprotein E (ApoE) has been examined immunohistochemically in the autopsied brains of middle-aged and old-aged control subjects, with and without amyloid beta protein (A beta) deposits, and of Alzheimer's disease patients. Senile plaques were consistently labeled with ApoE antiserum even in the very early stage of senile plaque formation seen in the fifth decade. In the cerebellar molecular layer, small dots of ApoE immunoreactivity, which were prominent in the Alzheimer's disease subjects, were observed in addition to immunoreactivity in diffuse plaques. ApoE antisera labeled all of the extracellular neurofibrillary tangles (NFT), whereas only a small minority of extracellular NFT were positive for A beta. A punctate pattern of ApoE immunoreactivity was seen at the media of the meningeal vessels lacking amyloid, when senile plaques were present in the nearby cortex. In the early stage of amyloid angiopathy, the distribution of ApoE immunoreactivity was much more extensive than that of A beta positivity. These findings suggest that ApoE accumulates in the early stage of senile plaque formation and, furthermore, that ApoE accumulation precedes A beta deposition in extracellular NFT and amyloid angiopathy.

Aged↗

PubMed1995

Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles.

Mutations of SOD-1 have recently been associated with autosomal dominant familial amyotrophic lateral sclerosis (ALS). A patient is described with a 20 year duration of motor neuron disease, with clinical features of ALS, who was heterozygous for a point mutation ATT to ACT leading to substitution of isoleucine for threonine at codon 113 in exon 4 of SOD-1. This mutation has previously been described in two families with ALS and three apparently sporadic cases of ALS. The patient described here had a family history suggestive of autosomal dominant inheritance of this genetic mutation; other members of the family having a more typical disease duration. Unusual pathological features included neurofibrillary tangles in neurons of the globus pallidus, substantia nigra, locus coeruleus, and inferior olivary nuclei, and absence of ubiquitin immunoreactive inclusions in motor neurons. This may reflect the slow progression of the neurodegeneration associated with the SOD-1 mutation in this patient. The prolonged survival, of over 20 years, with other family members having a more typical survival of two to three years, has important implications for genetic counselling in families with ALS in addition to the fundamental biological questions concerning the influence of these mutations on disease expression.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles.

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.

Aged↗

PubMed2005

Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer's disease.

Using the in vivo enzyme protection-enzyme inhibition method, we visualized the distribution of the intraventricularly and cisternally (cisterna magna) injected ambenonium chloride (Am) bound reversibly to the extracellular acetylcholinesterase enzyme (AChE) in the rabbit brain in order to describe the extracellular flow pathways from the cerebrospinal fluid (CSF). We found that the distribution of Am-protected AChE (indicating the Am itself) is similar to tracers having no intracerebral binding sites. The topographical distribution after both ways of application indicates a preferential penetration of Am into the limbic structures of the cerebral hemispheres in a predictable topographic sequence starting from the corticoid areas, allo- and periallo cortices followed by the mesocortical regions and then, in a limited extent, to the isocortex. The lentiform nuclei and the central part of diencephalic halves are inaccessible to Am. The hierarchic order in the sequence of diffusion from the CSF into the hemispheric subpial regions and the distribution pattern of Am resemble the stereotypic topographic expansion pattern and the predominantly limbic distribution of neurofibrillary tangles (NFTs) in Alzheimer's disease and related conditions.

Acetylcholinesterase↗

PubMed1999

Can secondary degeneration accelerate the formation of neurofibrillary tangles? A case of hemispheric infarction showing asymmetric degeneration of the substantia nigra, red nuclei, inferior olivary nuclei and dentate nuclei with concomitant changes of progressive supranuclear palsy.

A case of hemispheric infarction involving the territory of the right middle cerebral artery and the thalamus showed conspicuous asymmetric degeneration in the substantia nigra, red nuclei, inferior olivary nuclei and dentate nuclei with concomitant changes of progressive supranuclear palsy (PSP). The right substantia nigra and red nucleus showed loss of neurons and proliferation of astrocytes. The right olivary nucleus was hypertrophic, while the neuronal loss and astrocytosis in the dentate nucleus were predominant on the contralateral side. Modified Gallyas-Braak staining revealed the extensive distribution of neurofibrillary tangles (NFTs), threads and intraglial argyrophilic structures in the globus pallidus, subthalamic nuclei, cerebral cortex and dentate nuclei, as well as in the affected brain stem nuclei, with a distinct predominance on the affected side. In this case, the one-sided predominance of the extended degeneration in these brain stem and cerebellar areas is considered, in addition to the PSP changes, to be due to secondary retrograde degeneration via the nigrostriatal and dentato-rubro-thalamic pathways following the hemispheric infarction, and to also be the result of disruption of the dentato-olivary fiber connections. In addition, because of the predominant distribution of NFTs on the more degenerated side, it is surmised that the formation of NFTs may be accelerated by secondary degeneration.

Aged↗

PubMed1995

Calcineurin (phosphatase 2B) is present in neurons containing neurofibrillary tangles and in a subset of senile plaques in Alzheimer's disease.

The accumulation of hyperphosphorylated tau species in neurons in Alzheimer's disease (AD) might result from a relative decrease in their content of protein phosphatases. In this study we have investigated the immunocytochemical distribution of calcineurin (phosphatase 2B) in the hippocampus and temporal cortex of human control subjects and in AD. Calcineurin was strongly expressed in neuronal perikarya and dendrites but only weakly in white matter tracts, both in controls and in AD. The distribution of calcineurin was preserved in AD. By double-immunolabelling with calcineurin antibodies and the AT8 antibody to paired helical filament-tau, it was observed that a strong calcineurin immunoreactivity was still present in many neurons containing neurofibrillary tangles (NFT). Calcineurin was present in dystrophic neurites in some senile plaques (SP) located in the hippocampal formation but more rarely in neocortical areas; this calcineurin immunoreactivity did not always overlap with the tau immunoreactivity in SP. These results suggest that development of NFT in most neurons does not result from a major decrease of calcineurin expression.

Aged↗

PubMed1997

Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease.

Mutations in the presenilin-1 (PS1) gene is a cause of early- onset familial Alzheimer's disease (AD). Endogenous PS1 is associated with the endoplasmic reticulum in the cell body of undifferentiated SH-SY5Y neuroblastoma cells. At early stages of neuronal differentiation in rat hippocampal culture, PS1 appears in all neuritic processes and in growth cones. In mature differentiated neurons, PS1 is concentrated in the somatodendritic compartment but is also present at lower levels in axons. A similar localization of PS1 is observed in vivo in neurons of the adult human cerebral cortex. In sporadic AD, PS1 appears in the dystrophic neurites of mature amyloid plaques and co-localizes with a subset of intraneuronal neurofibrillary tangles (NFTs). About 30% of hippocampal NFTs are labeled with a highly specific antibody to the PS1 C-terminal loop domain but not with an antibody to the PS1 N terminus. This observation is consistent with a potential association of the PS1 C-terminal fragment with NFTs, because PS1 is constitutively cleaved to N- and C-terminal fragments in neurons. These results suggest that PS1 is highly expressed and broadly distributed during early stages of neuronal differentiation, consistent with a role for PS1 in neuronal differentiation. Furthermore, the co-localization of PS1 with NFTs and plaque dystrophic neurites implicates a role for PS1 in the diverse pathological manifestations of AD.

Alzheimer Disease↗