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PubMed2001

FE65 in Alzheimer's disease: neuronal distribution and association with neurofibrillary tangles.

FE65, a protein expressed in the nervous system, has the ability to bind the C-terminal domain of the amyloid precursor protein. This suggests a role for FE65 in the pathogenesis of Alzheimer's disease (AD). The present study was conducted to find out if the distribution of FE65 immunoreactivity was affected during the course of AD, and to determine the degree of co-localization of FE65 with other proteins known to be involved in AD. Single immunoperoxidase-labeling experiments, conducted on six sporadic AD patients and six nondemented age-matched controls, showed that the proportion of volume occupied by FE65 immunoreactivity was not modified in the isocortex of AD patients. However, in hippocampal area CA4, increased FE65 immunoreactivity seemed to be associated with the severity of the disease. Double-immunofluorescent labeling did not show any clear co-localization of FE65 with the amyloid precursor protein. FE65 immunoreactivity was also absent from focal and diffuse deposits of the beta-amyloid peptide. Unexpectedly double labeling experiments showed a co-localization of FE65 and tau proteins in intracellular tangles. Ultrastructural observations confirmed that FE65 was associated with paired helical filaments.

Aged↗
PubMed2003

Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.

Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.

Animals↗
PubMed1993

[A comparative study of six different staining methods on neurofibrillary tangles and senile plaques].

Six different staining methods were evaluated for demonstrating SPs and NFTs by using serial sections of brain tissue collected from aged patients with or without senile dementia. The methods used were as follows: the Bodian, Modified Beilschowsky, Periodic acid methenamine silver (PAMS), New methenamine silver (MS), PAS and Congo Red. SPs and NFTs were demonstrated in the cerebral cortex of aged patients with or without dementia. Among these 6 methods Bodian gives a more reliable result in demonstrating tangles and plaques of the classic and primitive types but not the diffuse type. The MS method clearly demonstrated all the 3 types of SPs particularly the diffuse plaque, but could not show the NFTs. The result indicates that combination of Bodian and MS methods seemed to be the most reliable method for routine neuropathological investigation.

Aged↗
PubMed1997

Neurofibrillary tangles in the dentate granule cells of patients with Alzheimer's disease, Lewy body disease and progressive supranuclear palsy.

Recent studies have shown that the dentate granular cells of the hippocampus are affected in patients with Alzheimer's disease (AD). To gain a better understanding of the cytoskeletal alterations in these cells, we carried out immunocytochemical and immunoelectron microscopic analysis of the dentate gyrus of patients with primary degenerative dementias, using a monoclonal antibody against paired helical filaments (TG3). This antibody labeled a large number of spherical inclusions in the dentate granule cells of patients with AD and its Lewy body variant (LBV). These inclusions consisted of straight tubular structures (about 18-25 nm in diameter), similar to those found in progressive supranuclear palsy (PSP). These inclusions, although in a smaller number, were also found in demented patients with PSP, but not in those with diffuse Lewy body disease or age-matched controls. These findings indicate that the neurofibrillary alterations in the dentate granule cells of patients with AD, LBV and PSP share cytoskeletal similarities.

Alzheimer Disease↗
PubMed1995

Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study.

Zinc appears to have a role in binding amyloid precursor protein in vitro, but it is not known whether zinc plays a role in senile plaque formation in vivo in humans. Serum zinc concentrations were available from 12 sisters who died in the Nun Study, a longitudinal study of aging and Alzheimer's disease. Fasting serum zinc concentrations, determined approximately 1 year before death, showed moderate to strong negative correlations with senile plaque counts in seven brain regions. In all brain regions combined, the age-adjusted negative correlations with serum zinc were statistically significant for total senile plaques and diffuse plaques, and suggestive for neuritic plaques. Thus serum zinc in the normal range may be associated with low senile plaque counts in the elderly.

Aged↗
PubMed2003

Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis.

Senile dementia of the NFT type (SD-NFT) is a subset of dementia in the elderly, characterized by numerous NFT in the hippocampal region and absence or scarcity of senile plaques throughout the brain. Senile dementia-NFT has also been referred to as tangle-only dementia, NFT-predominant form of SD, SD with tangles, or limbic NFT dementia. Herein are proposed the criteria for neuropathological diagnosis of SD-NFT: (i) late-onset dementia with abundant NFT in the hippocampal region and absence or scarcity of senile plaques (amyloid beta protein deposits) throughout the brain; and (ii) exclusion of other dementias with NFT. Some elderly individuals suffering from memory disorder without obvious dementia have neuropathological findings similar to SD-NFT, and they would represent a condition in the process of formation of the SD-NFT pathology. Guidelines for the clinical diagnosis of SD-NFT are also proposed; development of reliable diagnostic tests is necessary to differentiate AD and other neurodegenerative dementias from SD-NFT.

Aged↗
PubMed1998

[Microtubule-associated protein30 (MAP30) and ubiquitin detected in neurofibrillary tangles of Alzheimer's disease brains].

Using immunohistochemical technique, the distribution of immunoreactive products of antiubiquitin and MAP30 in the neurons of hippocampus of Alzheimer's disease (AD) brain were studied. Nurofibrillary tangles (NFT), dystrophic neurites in plaques and neuropil threads were labeled by the antibody of ubiquitin. NFT and pretangle neurons (PTN) were stained by the antibody of MAP30, but not detectable signal in axons or distal dendrites. The neurons immunostained with antibodies to ubiquitin and MAP30 were found in all the areas of CA1, CA2, CA3 and CA4 of hippocampus of AD. These neurons labeled by 2 antibodies used in this study were distributed more in the CA1 and CA2 than those in CA3 and CA4. The results indicate that ubiquitin is seen associated when NFT is already formed, and MAP30 may be a novel antigenic component of NFT in Alzheimer's disease.

Aged↗
PubMed2004

The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism.

Epidemiologic studies indicate that elderly women are at higher risk for Alzheimer disease compared to men. In order to pathologically verify this result, the extent of AD brain lesions (NFT and SP) was compared for men and women at each age, that is, at each decade from 25 years to 95 years, in a large sample of > 5000 routine autopsy cases. Women had more affected brain regions beginning in late middle age. They also had more extensive SP depositions throughout the brain compared to men at each early NFT stage I, II, and III. At later NFT stages IV, V, and VI both men and women had extensive SP deposits. The gender gap in SPs at early NFT stages was large and specific to women who carried the APOE4 allele (P <.001) and in addition to the acceleration in NFT stage also found for APOE4+ women.

Adult↗
PubMed1998

Absence of aluminium in neurofibrillary tangles in Alzheimer's disease.

Using the new technique of nuclear microscopy, aluminium is not detected in pyramidal neurons in brain tissue from Alzheimer's disease (AD) patients. The analytical technique of nuclear microscopy can simultaneously image and analyse features in unstained and untreated tissue sections. In tissue which had been previously subjected to conventional procedures such as fixation and osmication, aluminium was observed in both neurons and surrounding tissue. This result shows that the analysis of tissue prepared using conventional chemical techniques may produce contamination or elemental redistribution, and supports our previous investigations which implied that aluminium is not involved in the aetiology of AD. In addition, significant increases in iron, phosphorus and sulphur concentrations were noted between neurons from Alzheimer tissue and neurons from age-matched controls, and between the supporting Alzheimer tissue and supporting control tissue, implying an overall increase in these elements. No significant increase in calcium was observed between neurons from Alzheimer tissue and neurons from age-matched controls.

Aluminum↗
PubMed2004

The p53 homologue p73 accumulates in the nucleus and localizes to neurites and neurofibrillary tangles in Alzheimer disease brain.

The molecular mechanisms that regulate neuronal survival vs. death during Alzheimer disease (AD) remain unclear. Nonetheless, a number of recent studies indicate that increased expression or altered subcellular distribution of numerous cell cycle proteins during AD may contribute to disease pathogenesis. Because homologues of p53, a key regulatory protein in the cell cycle, such as p73, have been identified and shown to participate in cellular differentiation and death pathways, we examined the expression and distribution of p73 in the hippocampus of eight control and 16 AD subjects. In control subjects, hippocampal pyramidal neurones exhibit p73 immunoreactivity that is distributed predominately in the cytoplasm. In AD hippocampus, increased levels of p73 are located in the nucleus of pyramidal neurones and p73 is located in dystrophic neurites and cytoskeletal pathology. Immunoblot analysis confirmed the presence of p73 in the hippocampus. These data indicate that p73 is expressed within hippocampal pyramidal neurones and exhibits altered subcellular distribution in AD.

Aged↗
PubMed1993

Pathological overlap in cases of parkinsonism associated with neurofibrillary tangles. A study of recent cases of postencephalitic parkinsonism and comparison with progressive supranuclear palsy and Guamanian parkinsonism-dementia complex.

In recent years a number of patients suffering from long-standing postencephalitic parkinsonism have donated their brains to the United Kingdom Parkinson's Disease Society Brain Bank, in London. In view of the paucity of detailed neuropathological reports of the disease since the 1940s, we have carried out a clinicopathological study of eight recent cases. A spectrum of pathological change was seen, with highly variable involvement of cortical, subcortical and brainstem structures. There was no correlation between severity of disease and severity of pathology. The anatomical distribution of lesions was compared with that seen in progressive supranuclear palsy and Guamanian Parkinson-dementia complex. No definite histological features were identified that could distinguish any of the three disease entities. While the pathogenesis of postencephalitic parkinsonism, progressive supranuclear palsy and Guamanian Parkinson-dementia complex remains unknown, the presence of similar pathologies in these conditions suggests a common disease mechanism, despite the distinctive clinical features.

Aged↗
PubMed1995

Apolipoprotein E immunoreactivity within neurofibrillary tangles: relationship to Tau and PHF in Alzheimer's disease.

The present immunohistochemical study determined the relationship between ApoE and the expression of the cytoskeletal protein tau (Tau2) and paired helical filaments (PHF), within the magnocellular neurons of the nucleus basalis of Meynert and layer II stellate neurons of the entorhinal cortex in Alzheimer's disease (AD). Although nearly all ApoE immunoreactive perikarya within these two brain regions were PHF immunoreactive, not all PHF and Tau2 containing neurons stained for ApoE in AD. Moreover, more Tau2-immunostained neurons, as compared to PHF, were ApoE immunonegative. This was particularly evident in a population of control subjects which exhibited AD-like pathology intermediate between the AD and normal aged individuals. Thus, neurons within the nucleus basalis of Meynert and entorhinal cortex layer II stellate exhibit evidence of cytoskeletal pathology prior to displaying ApoE. These observations suggest that (1) ApoE plays a secondary role in NFT formation or (2) this protein is accumulated within these neurons in response to reparative process(es) induced by NFT-associated neuronal damage.

Aged↗
PubMedDate not supplied

Glycogen synthase kinase 3 alpha and 3 beta do not colocalize with neurofibrillary tangles.

Glycogen synthase kinase (GSK) 3 alpha and 3 beta are two proline-directed serine/ threonine kinases that have been shown in vitro to hyperphosphorylate tau, and therefore, may contribute to neurofibillary tangle (NFT) formation in Alzheimer's disease (AD). We report here that, in the human hippocampal formation of both control and AD individuals, GSK 3 alpha and 3 beta are immunohistochemically localized to neurons within the presubiculum > CA1, CA3, and CA4 subfields of the hippocampus, layers III > II > IV, V, VI of entorhinal cortex, and occasional neurons in layers III, V, and VI of temporal neocortex. By contrast, NFTs occur primarily in CA1. subiculum, layers II and IV of entorhinal cortex, and layers II, III, and V of temporal neocortex. The presubiculum and other subfields are frequently spared. Thus, localization of GSK 3 alpha and GSK 3 beta does not correspond to the expected pattern of neuronal vulnerability to NFT formation in AD. Interpreted within the limitations of immunohistochemical detection, these results argue against a major role of GSK 3 alpha or GSK 3 beta in NFT formation in AD.

Aged↗
PubMed1996

beta PP and Tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease.

Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43-residue peptide (termed A beta), which is derived from a 695- to 770-amino-acid precursor protein (termed beta PP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of beta PP770 (ie, the transmembrane region of beta PP distal to A beta) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of beta PP770 bound tau proteins. This beta PP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both molecules. These data suggest that beta PP or beta PP fragments containing the tau binding site are involved in the pathogenesis of PHFs in Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Two distinct subgroups of senile dementia of Alzheimer type: quantitative study of neurofibrillary tangles.

The heterogeneity of senile dementia of Alzheimer type (SDAT) has been suggested by some authors clinically and neuropathologically. The heterogeneity of SDAT was investigated based on quantification of NFT combining Braak and Braak's neuropathological staging and the density of NFT in various areas of the cerebral cortex. Brain tissues were examined from 16 autopsy cases with clinically late onset dementia (> age 65) and neuropathologically diagnosed dementia of Alzheimer type (DAT). Gallyas-Braak staining was used for the quantification of NFT. The density of NFT was examined in the precentral gyrus, middle temporal gyrus (T2), parahippocampal gyrus and the amygdaloid nucleus. The 16 cases studied were divided into two groups depending on the number of NFT in the cortex (cut-off score: 5/mm2): the AD-like group (NFT > or = 5/mm2) and the common group (NFT < 5/mm2). The density of NFT in the precentral gyrus (t(3.225) = -9.007, P = 0.002) and T2 (t(3.365) = -3.774, P = 0.027) in the AD-like group was significantly higher than those in the common group. However, no significant difference was observed in the parahippocampal gyrus between the two groups (t(14) = -0.318, NS). Moreover, there were no significant differences between the two groups as regards age at onset and the duration of the illness. The present study revealed the possible existence of two subgroups in SDAT having significantly different NFT densities in various areas of the cerebral cortex without any significant difference in their duration of illness. This classification has no relationship to Braak and Braak's staging, which depends only on the distribution of NFT, irrespective of their density. Arai et al. revealed that the NFT density in AD was significantly higher than in SDAT. We suggest that the neuropathological findings of the AD-like group in SDAT resemble those of presenile AD.

Age of Onset↗
PubMed1979

Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia.

A brief description is given of neurofibrillary changes of the paired helical filament type in a variety of chronic neurological diseases. These include subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Down syndrome, Hallervorden-Spatz disease, and lipofuscinosis. In these conditions, with the exception of Hallervorden-Spatz disease neurofibrillary changes were previously recognized but paired helical filaments were identified only in some cases. Moreover, in the present series, the age of patients at death was often younger than in previously recorded cases.

Adolescent↗
PubMedDate not supplied

Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis.

A battery of antisera that specifically stained the tangles of Alzheimer's disease also stained the tangles in all of 8 cases of dementia pugilistica (punch-drunk syndrome). Since the paired helical filament antigens found in Alzheimer type neurofibrillary degeneration are present in the tangles of dementia pugilistica the pathogenesis of tangle formation in these conditions is likely to be the same; thus head injury may be a predisposing factor or environmental trigger for Alzheimer's disease.

Adult↗