Biomedical subjects

P Cras

Publications and source records attributed to P Cras.

At least 73 records · Page 4Linked to original sources

PubMed1994

Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein.

Tau is a neuronal phosphoprotein the expression of which is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult human brain, with the fetal isoform corresponding to the shortest adult isoform. Phosphorylation is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer's disease, the six adult tau isoforms become hyperphosphorylated and form the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions. One way to identify phosphorylated sites in tau is to use antibodies that recognize phosphorylated residues within a specific amino acid sequence. We here characterize the two novel phosphorylation-dependent anti-tau antibodies AT270 and AT180 and identify their epitopes as containing phosphorylated Thr-181 and Thr-231 respectively. With these antibodies we show that these two threonine residues are partially phosphorylated in fetal and adult tau and almost fully phosphorylated in PHF tau. This result contrasts with previous studies of Ser-202 and Ser-396 which are partially phosphorylated in fetal tau, unphosphorylated in adult tau but almost fully phosphorylated in PHF tau.

Alzheimer Disease↗

PubMed1994

Bilateral infarction in the anterior cerebral artery vascular territory due to an unusual anomaly of the circle of Willis.

BACKGROUND: Bilateral infarction in the anterior cerebral artery vascular territory is rare and usually results from rupture of an aneurysm of the anterior communicating artery. In the case of an anomaly of the anterior part of the circle of Willis, thrombosis also may lead to bilateral infarction. CASE DESCRIPTION: A 73-year-old right-handed man presented with a complete loss of communicative behavior and an almost complete quadriplegia. 99mTc-hexamethylpropyleneamine oxime single-photon emission-computed tomography (HMPAO SPECT) of the brain showed a "horseshoe" image, reflecting bilateral perfusion defects in areas supplied by the anterior cerebral arteries. Postmortem examination of the brain revealed an unusual anomaly of the circle of Willis in which the postcommunicating part of the right anterior cerebral artery was absent. CONCLUSIONS: In our patient a unique developmental anomaly of the circle of Willis indirectly contributed to bilateral infarction in the territory of the anterior cerebral artery. The patient's neuropsychological profile, dominated by akinetic mutism, was highly suggestive of involvement of the receptive language modalities. For the first time, 99mTc-HMPAO SPECT of the brain revealed a horseshoe image in bilateral infarction in the territory of the anterior cerebral artery.

Aged↗

PubMed1994

Microtubule-associated protein tau epitopes are present in fiber lesions in diverse muscle disorders.

The microtubule-associated protein tau is a major cytoskeletal protein involved in the neurofibrillary tangles of Alzheimer's disease. Although tau is predominantly a neuronal protein, it has been demonstrated in glia and other nonneuronal cells. We describe the presence of microtubule-associated protein tau epitopes in various muscle fiber lesions in oculopharyngeal and Becker muscular dystrophy, dermatomyositis, central core disease, neurogenic atrophy, and in the recovery phase of an attack of malignant hyperthermia. Western blot demonstrated a 100- to 110-kd tau-immunoreactive protein probably corresponding to 'big tau' as described in peripheral nerves. Tau immunoreactivity in muscle fiber lesions usually co-localized with tubulin, although electron microscopy failed to show an increase in microtubules. Tau and tubulin reactivity also correlated with the presence of desmin and vimentin epitopes. Possible explanations for the presence of tau are briefly discussed.

Adult↗

PubMed1994

Eosinophilia myalgia syndrome: absence of immunoglobulin reactivity suggests a cellular rather than humoral mechanism.

The idiopathic disorder Eosinophilia Myalgia Syndrome (EMS), characterized by peripheral eosinophilia, myalgia and frequently fasciitis, can be triggered by ingestion of some commercial preparations of L-Tryptophan. Activated T-lymphocytes and macrophages are involved in the pathogenesis of EMS. We investigated immunohistochemically the potential role of immunoglobulins and of the terminal C5b-9 complement factor (membrane attack complex) in EMS. We found no evidence for direct involvement of immunoglobulins. However, membrane attack complex immunoreactivity was present in vessel walls in EMS, but completely absent in controls. These observations suggest that the fasciitis in EMS involves a cellular rather than a humoral reaction and that complement activation could be of importance.

Adult↗

PubMed1993

Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease.

In cerebral amyloid angiopathy, the amyloid-beta (A beta) deposits lie primarily in the tunica media suggesting that smooth muscle cells play an important role in A beta deposition. To define this role, we conducted an immunocytochemical study of brain tissue from cases of Alzheimer disease with extensive cerebral amyloid angiopathy and cerebral hemorrhage. Antibodies specific to recombinant beta protein precursor (beta PP) and synthetic peptides homologous to various beta PP sequences from residue 18 to 689 of beta PP695 were used. Antibodies to actin, tropomyosin, alpha-actinin or desmin were used to label muscle cells. Antibodies to A beta sequences intensely recognized the extracellular amyloid deposit. Antibodies raised against beta PP sequences other than the A beta domain recognized smooth muscle cells. beta PP-immunoreactivity was reduced in regions of A beta deposits, since no muscle cells were recognized by cytoskeletal markers or observed ultrastructurally. In order to assess why A beta is deposited in the tunica media, we used biotin-labelled beta PP to determine if beta PP can be locally retained. We found beta PP bound to the tunica media of vessels but not other brain elements. These findings suggest A beta in blood vessels derives from degenerating beta PP-containing smooth muscle cells.

Actinin↗

PubMed1993

The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development.

Tau is a neuronal phosphoprotein whose expression is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult brain, with the fetal isoform corresponding to the shortest of the adult isoforms. Phosphorylation of tau is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer disease, the six adult tau isoforms become abnormally phosphorylated and form the paired helical filament, the major fibrous component of the characteristic neurofibrillary lesions. We show here that Ser-202 (in the numbering of the longest human brain tau isoform) is a phosphorylation site that distinguishes fetal from adult tau and we identify it as one of the abnormal phosphorylation sites in Alzheimer disease. The abnormal phosphorylation of tau at Ser-202 in Alzheimer disease thus recapitulates normal phosphorylation during development.

Adult↗

PubMed1993

The phosphatase inhibitor okadaic acid induces a phosphorylated paired helical filament tau epitope in human LA-N-5 neuroblastoma cells.

Recently, a mitogen activated protein kinase has been implicated in the generation of a phosphorylated paired helical filament (PHF) epitope recognized by the monoclonal antibody AT8. This epitope consists of phosphorylated serines 199 and/or 202 of the human microtubule associated protein tau. Theoretically, aside from abnormal kinase activity, inhibition of phosphatase activity could also be involved in the abnormal phosphorylation status of the microtubule associated protein tau. To investigate this, we incubated LA-N-5 neuroblastoma cells with okadaic acid, a specific inhibitor of phosphatase 2A. We found that incubating neuroblastoma cells with okadaic acid induces the abnormally phosphorylated AT8 epitope. The effect of okadaic acid is time and dose dependent and is reversible. Our findings suggest that phosphatase activity is important in the regulation of the phosphorylation state of tau. Phosphatases may act directly on tau or may influence the activity of mitogen activated protein kinase. Incubation of LA-N-5 neuroblastoma cells with okadaic acid provides a cellular model in which the generation of a well-defined PHF-tau epitope can be investigated.

Epitopes↗

PubMed1993

Rimmed vacuoles of inclusion body myositis and oculopharyngeal muscular dystrophy contain amyloid precursor protein and lysosomal markers.

Rimmed vacuoles are small areas of focal destruction of muscle fibres, found in inclusion body myositis, oculopharyngeal muscular dystrophy and other muscle disorders. They are known to contain amyloid proteins, probably of beta-amyloid type. We examined rimmed vacuoles immunohistochemically in 12 patients with inclusion body myositis and two patients with oculopharyngeal muscular dystrophy with antibodies to beta-amyloid precursor protein and cathepsin B and D. We found evidence for the presence of all these markers in rimmed vacuoles. These results confirm the presence of beta-amyloid in rimmed vacuoles, and provide additional support for the hypotheses that rimmed vacuoles are of lysosomal origin and that lysosomes are probably important in the metabolism of amyloid precursor protein.

Aged↗

PubMed1993

Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay.

Alzheimer's disease is a progressive degenerative dementia characterized by the abundant presence of neurofibrillary tangles in neurons. This study was designed to test whether the microtubule-associated protein tau, a major component of neurofibrillary tangles, could be detected in CSF. Additionally, we investigated whether CSF tau levels were abnormal in Alzheimer's disease as compared with a large group of control patients. We developed a sensitive sandwich enzyme-linked immunosorbent assay using AT120, a monoclonal antibody directed to human tau, as a capturing antibody. With this technique, the detection limit for tau was less than 5 pg/ml of CSF. Using AT8, which recognizes abnormally phosphorylated serines 199-202 in tau, the detection limit was below 20 pg/ml of CSF. However, with AT8, we found no immunoreactivity in CSF, suggesting that only a small fraction of CSF tau contains the abnormally phosphorylated AT8 epitope. Our results indicate that CSF tau levels are significantly increased in Alzheimer's disease. Also, CSF tau levels in a large group of patients with a diversity of neurological diseases showed overlap with CSF tau levels in Alzheimer's disease.

Adolescent↗

PubMed1992

Serial reconstruction of beta-protein amyloid plaques: relationship to microvessels and size distribution.

The suggestion that the amyloid plaques in Alzheimer disease are formed by abnormal leakage from microvessels is mainly based on the finding that many plaques are topographically associated with microvessels. However, because the microvessel network is dense and amyloid plaques are numerous, the frequently observed association may result from chance contact, especially for larger plaques. Therefore, we determined the frequency of this association as a variable of plaque size. If all the amyloid plaques are associated with microvessels, a constant and high rate of association would be expected for all plaque sizes. On the other hand, if the association is a chance contact, larger plaques would show more frequent contact than smaller ones. Sections were double-immunostained for amyloid plaques and microvessels with antibodies raised against beta-protein and collagen type IV, respectively. Amyloid plaques were reconstructed using 12 serial sections (7 microns thick) from the entorhinal cortex of two Alzheimer patients. With reconstruction we determined the size distribution of amyloid plaques as well as the influence of size on vascular association. All the amyloid plaques larger than 42 microns were associated with microvessels, however, the smaller the amyloid plaques, the less frequently they were associated with microvessels. Interestingly, although diffuse amyloid plaques occur in all size classes, core-containing amyloid plaques have a more discrete size. We conclude that the topographical relationship between amyloid deposition and capillaries does not support the leakage theory for amyloid plaque formation.

Aged↗

PubMed1992

Basic fibroblast growth factor binds to filamentous inclusions of neurodegenerative diseases.

The extracellular matrix protein heparin sulfate proteoglycans (HSPG) has been found in the neurofibrillary pathology of Alzheimer disease. This study was performed to determine if similar proteoglycans might be present in the fibrillary inclusions of other neurodegenerative diseases. Basic fibroblast growth factor (bFGF) binding to heparinase sensitive sites was used as an assay for HSPGs. We found that the inclusions of Pick and Parkinson diseases as well as progressive supranuclear palsy contained heparinase sensitive bFGF binding sites while the inclusions of diffuse Lewy body disease lacked bFGF binding sites. These findings indicate that HSPG's interactions and possible role in the formation of intraneuronal inclusions are not limited to Alzheimer disease.

Aged↗

PubMed1992

Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene.

Several families with an early-onset form of familial Alzheimer's disease have been found to harbour mutations at a specific codon (717) of the gene for the beta-amyloid precursor protein (APP) on chromosome 21. We now report, a novel base mutation in the same exon of the APP gene which co-segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy. The mutation results in the substitution of alanine into glycine at codon 692. These results suggest that the clinically distinct entities, presenile dementia and cerebral amyloid angiopathy, can be caused by the same mutation in the APP gene.

Adult↗

PubMed1992

Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3.

Genetic linkage studies with chromosome 21 DNA markers and mutation analysis of the beta-amyloid protein precursor gene located in 21q21.3 have indicated that early-onset Alzheimer's disease (EOAD) is a heterogeneous disorder for which at least one other chromosomal locus exists. We examined two extended histopathologically confirmed EOAD pedigrees, AD/A and AD/B, with highly informative short tandem repeat (STR) polymorphisms and found complete linkage of the disease to a (CA)n dinucleotide repeat polymorphism at locus D14S43 in 14q24.3 (Zmax = 13.25 at theta = 0.0). Using additional chromosome 14 STR polymorphisms we were able to delineate the region containing the EOAD gene to an area of, at most, 8.9 centiMorgans between D14S42 and D14S53, flanking D14S43 on both sides.

Adult↗

PubMed1992

Transient musical hallucinosis of central origin: a review and clinical study.

A 52 year old, right handed, hearing impaired woman was admitted with headache and neck stiffness. The only neuropsychological symptom was transient auditory perceptions in the left ear, which were musical, seemed familiar and were not influenced by verbal communication. CT and MRI showed a right subarachnoid haemorrhage, while brainstem auditory evoked potentials failed to reveal a brainstem lesion. In patients with organic cerebral disease, unilateral auditory hallucinations (AHs) may indicate a lesion in the contralateral hemisphere. However, according to this review the type of AHs (verbal versus musical) is not consistently associated with a cerebral lesion on either side.

Auditory Perception↗

PubMed1992

[Problems with flute playing: an otological problem? Case report of a peculiar cerebellar astrocytoma].

A rare case of cerebellar astrocytoma presenting as a cerebellopontine angle tumour is discussed. A 35-year old woman noticed a bizarre twitching and fatigability of the left upper lip while playing the flute. There was also a mild hearing loss on the left side and she sometimes felt unsure of herself when walking. A thorough examination by means of speech audiometry, electronystagmography, ABR, CT-scan and MRI revealed a large, partly calcified mass occupying the cerebellopontine angle. Only the histological examination of the surgical specimen revealed the true nature of the tumour. The special characteristics of this tumour and the unusual clinical course are discussed. The importance of a good histological diagnosis is stressed.

Adult↗

PubMed1992

Subcellular localization of amyloid precursor protein in senile plaques of Alzheimer's disease.

The authors have previously shown that amyloid precursor protein (APP) accumulates in neurites present in senile plaques of Alzheimer's disease (AD). In this ultrastructural immunocytochemical study, we describe the subcellular site of APP accumulation. Vibratome sections of glutaraldehyde-paraformaldehyde fixed hippocampi from five cases of AD were pretreated with methanol and immunostained with an antibody raised against recombinant APP 770 by using either indirect immunogold or peroxidase methods. Immunolabeling was localized in cell processes filled with amorphous, irregular-shaped materials, which were identified as dense bodies deformed by postmortem autolysis and methanol treatment, as well as multilamellar membranous bodies. Identification of these bodies was obtained with comparative ultrastructural examination of biopsy and autopsy tissue fixed with and without methanol treatment. These electron-dense organellae were positive for the lysosomal marker, acid phosphatase. At light microscopy, acid phosphatase and APP colocalized to the same cell processes in senile plaques. Many of those cell processes contained abnormal straight or paired helical filaments supporting their neuritic nature. These results suggest that APP accumulates in the lysosomal system of the dystrophic neurites present in senile plaques and are consistent with a neuronal origin of the APP forming the amyloid in senile plaques.

Acid Phosphatase↗

PubMed1992

Beta protein immunoreactivity is found in the majority of neurofibrillary tangles of Alzheimer's disease.

The presence of dystrophic neurites in most extracellular neurofibrillary tangles (E-NFT) suggests a factor promoting neurite growth in E-NFT. Although the beta-protein detected in E-NFT may fill that role, reports that only 2-10% of E-NFT contain beta-protein whereas 80-100% contain dystrophic neurites suggested that beta-protein does not play an important role. In this study, the authors used two antisera and one monoclonal antibody to beta-protein to establish the effects of tissue preparation and formic acid enhancement on the detection of beta-protein in E-NFT. We found that beta-protein epitopes in E-NFT are sensitive to formaldehyde fixation and are best enhanced by 50% formic acid, whereas beta-protein in senile plaques is best enhanced at higher formic acid concentrations. After treatment with 50% formic acid, beta-protein was found in all E-NFT. Interestingly, after treatment with 10% formic acid, half of intraneuronal-NFT (I-NFT) also contained beta-protein immunoreactivity. The finding that beta-protein immunoreactivity in senile plaques, E-NFT and I-NFT is increased at different formic acid concentrations suggests that beta-protein in each location is in a different conformation. In contrast, no beta-protein immunoreactivity could be found in E-NFT of the brain stem, an area in which dystrophic neurites do not infiltrate E-NFT. These findings indicate a correlation between neuritic infiltration and presence of beta-protein in E-NFT and suggests the two are linked in Alzheimer's disease for E-NFT as well as senile plaques.

Aged↗

PubMed1991

Dystrophic neurites infiltrate extracellular neurofibrillary tangles in Alzheimer disease.

The neurotrophic activity of beta-amyloid protein (beta-AP) has been suggested to be responsible for the dystrophic neurites that surround beta-AP deposits in senile plaques of Alzheimer disease. The recent finding that neurofibrillary tangles (NFT) that remain as remnants in the extracellular space (E-NFT) after the death of the neuron contain beta-AP, suggested that dystrophic neurites might also be associated with E-NFT. In this study, we use a probe for E-NFT, basic fibroblast growth factor (bFGF)-binding to show that E-NFT do contain dystrophic neurites. Since these neurites contain the amyloid precursor protein whose cleavage can lead to beta-AP, they may also play a role in further beta-AP deposition in the E-NFT.

Aged↗