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1.
Dunckley T Beach TG Ramsey KE Grover A Mastroeni D Walker DG LaFleur BJ Coon KD Brown KM Caselli R Kukull W Higdon R McKeel D Morris JC Hulette C Schmechel D Reiman EM Rogers J Stephan DA 《Neurobiology of aging》2006,27(10):1359-1371
Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD. 相似文献
2.
The contribution that oligosaccharides might make to the structure of the senile plaque and the neurofibrillary tangle was investigated using lectin histochemistry in 9 patients with Alzheimer's disease. One group of 4 lectins diffusely stained the neurites of senile plaques whereas two groups of 6 different lectins stained neurofibrillary tangles within neuronal perikarya and plaque neurites. Neuraminidase pretreatment abolished staining of tangles by one of these latter groups, but did not affect staining by the other group. Senile plaque core amyloid failed to stain with any lectin. It is concluded that oligosaccharides may contribute, but in different ways, to glycoprotein or glycolipid residues that form an integral part of the structure of the senile plaque and the neurofibrillary tangle. 相似文献
3.
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. 相似文献
4.
Alzheimer's disease: neurofibrillary tangles in nuclei that project to the cerebral cortex 总被引:1,自引:0,他引:1
We have used an antibody to the paired helical filament protein to immunohistochemically identify the regional distribution of subcortical nuclei containing neurofibrillary tangles in brains from Alzheimer's disease patients. Sections were examined from the cerebral cortex, diencephalon, midbrain and pons in seven Alzheimer's and three age-matched normal brains. The antibody sensitively stained the many tangles, and senile plaques, in the cerebral cortex of the Alzheimer's brains and the few tangles and senile plaques in the aged normal cortex. Ten subcortical nuclei contained many tangles in the Alzheimer's brains. The tangles were found not only within the locus coeruleus and dorsal raphe nucleus, which often have been shown to be involved in Alzheimer's neuropathology, but also within several other nuclei not previously related to this disease. For example, tangles were found in the nucleus paranigralis, peripeduncular nucleus, medial parabrachial nucleus and several midline thalamic nuclei. All of the nuclei which contained tangles have been shown, in neuroanatomical tracing studies, to project to the cerebral cortex. These data indicate that Alzheimer's disease is a disease of the cerebral cortex and the numerous subcortical nuclei which diffusely innervate it, and are consistent with the hypothesis that the cerebral cortex is the primary target of the disease and the interconnected subcortical nuclei are secondarily affected due to retrograde transport of a cortical pathogen or failure of normal transport of a trophic agent. 相似文献
5.
In 4 cases of Alzheimer's disease (AD) a tau antiserum immunostained thin, round or flame-shaped profiles disposed around the nuclei of the cerebellar fusiform-type Golgi cells. In adjacent sections either a Bodian silver method or Congo red failed to reveal any abnormal structures. Since normal tau immunoreactivity is located on axons and is absent in formalin-fixed tissue, the tau-reactive profiles are likely to correspond to small masses of abnormal filaments, antigenically similar to those composing neurofibrillary tangles (NFT). This observation indicates that in AD the NFT formation is more diffuse than that showed with conventional histological methods. 相似文献
6.
A4 amyloid protein immunoreactivity is present in Alzheimer's disease neurofibrillary tangles 总被引:12,自引:0,他引:12
Neurofibrillary tangles and neuritic plaques are the neuropathological hallmarks of Alzheimer's disease. The latter consist of a core of A4 amyloid protein. We now report that some neurofibrillary tangles ('tombstone tangles') are also A4 immunoreactive. This observation is consistent with the hypothesis that A4 amyloid accumulation is a component of both neurofibrillary tangles and neuritic plaques. 相似文献
7.
Mark A Lovell J David Robertson Bruce A Buchholz Chengsong Xie William R Markesbery 《Neurobiology of aging》2002,23(2):179-186
The time course of formation of neurofibrillary tangles (NFT) and senile plaques (SP) in Alzheimer's disease (AD) brain is unknown. Above ground nuclear weapons testing in the late 1950s and early 1960s led to significantly increased levels of 14C in the atmosphere and carbon cycle. Because the amyloid beta peptide of SP and paired helical filaments of NFT, once formed, are relatively resistant to degradation, 14C levels observed in SP and NFT should reflect their year of formation. The purpose of this study was to develop a method to determine whether 14C levels could be used to define NFT and SP ages. Using accelerator mass spectrometry to measure bomb-pulse 14C levels, we determined the average age of formation of isolated SP and NFT fractions in bulk brain samples of 6 AD subjects. Although preliminary, the results demonstrate that it is possible to use bomb pulse 14C to determine the average year of formation of NFT and SP in the brain in AD. In addition, the data show that these structures, once formed, have a much slower carbon turnover rate than normal brain and are not in a formation/enzymatic degradation equilibrium. 相似文献
8.
Neurofibrillary tangles (NFT) are present in the subthalamic nucleus (STN) of progressive supranuclear palsy and corticobasal degeneration, two sporadic tauopathies with preferential accumulation of tau with four repeats in the microtubule binding domain (4R tau). Since recent evidence suggests that argyrophilic grain disease (AGD) is also a 4R tauopathy, we hypothesized that the STN may also be affected in AGD. Tau immunostaining was used to evaluate NFT in the STN in 18 cases of AGD compared with 18 non-AGD cases matched for age, sex and Braak stage. AGD cases had significantly more NFT in the STN than non-AGD cases (P=0.008) with no relationship between NFT score and Braak stage. Surprisingly, NFT were also found in the STN of some non-AGD cases, notably in cases with advanced Braak stage (i.e. Alzheimer's disease). When AGD and non-AGD were considered as a whole there was a correlation between neurofibrillary degeneration in the STN and Braak stage. This study demonstrates that neurofibrillary degeneration is frequent in the STN in AGD, but also detected in non-AGD cases with advanced Braak stage. 相似文献
9.
FE65 in Alzheimer's disease: neuronal distribution and association with neurofibrillary tangles
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Delatour B Mercken L El Hachimi KH Colle MA Pradier L Duyckaerts C 《The American journal of pathology》2001,158(5):1585-1591
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. 相似文献
10.
beta PP and Tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease. 总被引:1,自引:0,他引:1
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G. Giaccone B. Pedrotti A. Migheli L. Verga J. Perez G. Racagni M. A. Smith G. Perry L. De Gioia C. Selvaggini M. Salmona J. Ghiso B. Frangione K. Islam O. Bugiani F. Tagliavini 《The American journal of pathology》1996,148(1):79-87
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. 相似文献
11.
Human neuroblastoma cells treated with aluminium express an epitope associated with Alzheimer's disease neurofibrillary tangles. 总被引:1,自引:0,他引:1
A number of studies have implicated aluminium as a possible factor in the pathogenesis of Alzheimer's disease (AD). Following an examination of the uptake of aluminium by human neuroblastoma cells in culture, treated with a range of concentrations of aluminium complexed with ethylene-diaminetetra-acetic acid (EDTA), we have now carried out an immunocytochemical study. Using an antibody to phosphorylated tau protein, which reacts specifically with AD neurofibrillary tangles (NFT), we have found that after treatment periods of 16 days to 8 weeks with aluminium-EDTA, the cells show positive staining with this antibody. No such reaction was detected in cells grown in medium alone, nor in aluminium-EDTA-treated cells subjected to the same immunocytochemical procedure but without added primary antibody. Cells grown in medium plus EDTA, which contains a low level of aluminium contamination, showed a slight reaction. Our system may provide a suitable model for studying the early changes which lead to NFT formation. 相似文献
12.
Properties of antigenic determinants that distinguish neurofibrillary tangles in progressive supranuclear palsy and Alzheimer's disease 总被引:3,自引:0,他引:3
M L Schmidt V M Lee H Hurtig J Q Trojanowski 《Laboratory investigation; a journal of technical methods and pathology》1988,59(4):460-466
Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and in progressive supranuclear palsy (PSP) differ in their location and morphology, but both appear to express the same or similar epitopes. These immunologic data may signify that both types of NFTs contain the same components and arise as a result of the same mechanisms. To explore this hypothesis, we probed PSP and AD samples of brain stem, where both PSP and AD NFTs occur, using a large panel of monoclonal antibodies (MAbs). The epitopes expressed in brain stem PSP and AD NFTs were compared with those in the NFTs of AD hippocampus. NFTs in PSP hippocampus were too infrequent for comparative analysis. The MAbs were raised to neurofilament and tau proteins, or to AD paired helical filaments. All MAbs raised to tau (three) and paired helical filaments (two) recognized brain stem PSP NFTs and AD NFTs in brain stem and hippocampus. However, 12 anti-NF MAbs specific for multiphosphorylation repeat domains or other phosphate-dependent and independent epitopes did not bind PSP NFTs, but they did detect AD NFTs in hippocampus, and 5 of these MAbs also recognized brain stem AD NFTs. We conclude that some populations of AD NFTs contain antigenic determinants that are not found in PSP NFTs. This may reflect the effect of different pathologic events specific to PSP and AD, or the selective formation of NFTs in different groups of neurons in each of these disorders. 相似文献
13.
The relevance of plaques and tangles to the study of Alzheimer's disease is considered. Recent results concerning isoforms of microtubule-associated protein tau, their expression and incorporation into paired helical filaments, are discussed. 相似文献
14.
Immunocytochemical evidence that the beta-protein precursor is an integral component of neurofibrillary tangles of Alzheimer's disease. 总被引:1,自引:1,他引:0
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G. Perry P. L. Richey S. L. Siedlak M. A. Smith P. Mulvihill D. A. DeWitt J. Barnett B. D. Greenberg R. N. Kalaria 《The American journal of pathology》1993,143(6):1586-1593
Amyloid beta (A beta) immunoreactivity has been demonstrated in all extracellular neurofibrillary tangles (E-NFT) and most intraneuronal neurofibrillary tangles (I-NFT). We undertook this immunocytochemical study to understand the relationship between A beta immunoreactivity localized in NFT and beta-protein precursor (beta PP). We found epitopes of amino-, mid-, and carboxyl-terminal domains of beta PP in I-NFT and the majority of E-NFT. NFT retained beta PP after ionic detergent extraction, demonstrating that beta PP is an integral component of NFT. Finding beta PP in regions of A beta immunoreactivity raises the possibility that beta PP or its fragments associate with amyloid, and that the stability of A beta is responsible for its dominance in amyloid deposits. 相似文献
15.
Jagoda Makjanic Brendan McDonald Christopher Philip Li-Hsian Chen Frank Watt 《Neuroscience letters》1998,240(3):485-126
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. 相似文献
16.
Implications of presenilin 1 mutations in Alzheimer's disease. 总被引:1,自引:0,他引:1
H Komano S Sudoh Y Kawamura R Wang K Yanagisawa 《Mechanisms of ageing and development》1999,107(3):281-298
Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are the most common genetic factors underlying the development of early-onset familial Alzheimer's disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1(M146L or deltaexon 10) under the control of the Lac repressor. Using this inducible PS1 system, the influence of PS1 mutations on the generation of endogenous murine Abeta species was assessed using a highly sensitive immunoblotting technique. The induction of mutated PS1 resulted in an increase in the extra- and intracellular levels of two distinct Abeta species ending at residue 42, Abeta1-42 and its N-terminally truncated variant(s), Abetax-42. In addition, the intracellular generation of these Abeta42 species was completely blocked by brefeldin A. In contrast, it exhibited differential sensitivities to monensin such that there was an increased accumulation of intracellular Abetax-42 but an inhibition of intracellular Abeta1-42 generation. These data strongly suggest that Abetax-42 is generated in a proximal Golgi compartment, whereas Abeta1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific gamma-secretase cleavage which occurs (i) in the ER or the early Golgi apparatus prior to gamma-secretase cleavage, or (ii) in the distinct sites where Abetax-42 and Abeta1-42 are generated. To date, the site of Abeta42 generation has not been firmly established. Our data provide new information regarding the site of Abeta42 generation mediated by the FAD-linked mutant PS1. 相似文献
17.
In Alzheimer's disease the Golgi apparatus of a population of neurons without neurofibrillary tangles is fragmented and atrophic. 总被引:4,自引:5,他引:4
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Recent immunocytochemical and morphometric studies in amyotrophic lateral sclerosis, Alzheimer's disease (AD), and aging indicate that the neuronal Golgi apparatus is a reliable index of activity or degeneration. To further evaluate a possible role of the Golgi apparatus in the pathogenesis of AD, we examined by double labeling the neuronal Golgi apparatus, neurofibrillary tangles (NFTs), and senile plaques (SPs) in the hippocampus of six cases of AD, and in 13 controls including three cases of a rare form of dementia lacking distinctive histopathological features. The Golgi apparatus was visualized with a polyclonal antiserum against MG-160, a membrane sialoglycoprotein of the organelle, and NFTs and SPs were visualized with biotinylated basic fibroblast growth factor (bFGF). Only a rare SP contained a few small immunostained elements of the Golgi apparatus. Neurons with intracellular NFTs, labeled with biotinylated bFGF, contained intensely labeled but deformed Golgi apparatus, which was displaced by the NFTs and coalesced into larger irregular granules. In contrast, a population of neurons without NFTs displayed fragmentation of the Golgi apparatus, ie, the organelle appeared in the form of small round, disconnected, and dispersed elements instead of the normal perinuclear network of irregular or linear profiles which often extended into the proximal segments of dendrites. In addition, the fragmented neuronal Golgi apparatus was atrophic as the percentage of the cell surface area occupied by the organelle was 4.4 +/- 0.6% SD, whereas in neurons with a normal Golgi apparatus the percentage of the cell surface area occupied by the organelle was 10.3 +/- 0.3% SD. The results of this study suggest that in AD the Golgi apparatus of a population of neurons without NFTs is involved in the pathogenesis of the disease. Considering the role of the Golgi apparatus in the processing of polypeptides destined for fast axoplasmic transports, the fragmentation of the organelle may be associated with functional and structural impairments of axons and presynaptic terminals. 相似文献
18.
Based upon our previous finding of the association of apolipoprotein E (apoE) immunoreactivity with cerebral amyloids and neurofibrillary tangles (NFTs), we examined immunohistochemically whether this is also the case for apolipoprotein B (apoB). Polyclonal antibody to apoB immunosustained senile plaque amyloid, vascular amyloid, subpial amyloid deposits and intracellular NFTs in formalin-fixed, paraffin-embedded brain sections from patients with Alzheimer disease. Hydrated autoclave pretreatment of the sections enhanced the staining of plaque amyloid. The results may suggest a role of apoB in amyloid and NFT formation. 相似文献
19.
The numerical density of senile plaques (SP) and neurofibrillary tangles (NFT) as revealed by the Glees silver method was compared with SP and NFT revealed by the Gallyas method and with amyloid (A4) deposits in immunostained sections in 6 elderly cases of Alzheimer's disease. The density of NFT was generally greater and A4 lower in tissue from hippocampus compared with the neocortex suggesting that A4 deposition was less important than the degree of paired helical filament (PHF) related damage in the hippocampus. The density of Glees SP was positively correlated Gallyas SP weakly correlated with A4 deposit number. A stepwise multiple regression analysis which included A4 deposit and Gallyas SP density and accounted for 54% of the variation in Glees SP density. Hence, different populations of SP were revealed by the different staining methods. The results suggested that the Glees method may stain a population of SP in a region of cortex where both amyloid deposition and neurofibrillary changes have occurred. 相似文献
20.
Monoclonal antibodies to Alzheimer neurofibrillary tangles. 1. Identification of polypeptides. 总被引:6,自引:4,他引:6
Ten monoclonal antibodies to Alzheimer neurofibrillary tangles (ANTs) were produced by immunizing mice with a brain homogenate from senile dementia of the Alzheimer type (SDAT). In methanol-fixed isolated neuronal perikarya, six of these antibodies reacted with nearly every ANT, three recognized 70-88% of ANTs, and one bound to less than 30% of ANT. In paraffin sections, three of the antibodies did not bind to tangles that had been fixed in formalin, three stained weekly, and four reacted with tangles in tissues that had been in formalin for more than a decade. Immunoblotting of brain homogenates showed that all but one antibody reacted with proteins from SDAT samples insoluble in SDS and too large to enter even the 3% polyacrylamide stacking gel. Polypeptides extractable by Tris buffer of molecular weight 58, 66, and 70 kd were detected in both normal and SDAT brains by two antibodies and only in SDAT brain by two other antibodies. One antibody did not show any reaction on the immunoblot. The results demonstrate that the epitopes recognized by these antibodies are not identical and that ANTs contain unique antigenic determinants as well as determinants in common with normal brain. Whether the unique determinants are acquired during tangle development or are essential in tangle formation remains to be investigated. 相似文献