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Biomedical subjects

D M Mann

Publications and source records attributed to D M Mann.

At least 109 records · Page 6Linked to original sources
PubMed1990

Negative regulation of transforming growth factor-beta by the proteoglycan decorin.

Decorin is a small chondroitin-dermatan sulphate proteoglycan consisting of a core protein and a single glycosaminoglycan chain. Eighty per cent of the core protein consists of 10 repeats of a leucin-rich sequence of 24 amino acids. Similar repeats have been found in two other proteoglycans, biglycan and fibromodulin, and in several other proteins including Drosophila morphogenetic proteins. Expression of high levels of decorin in Chinese hamster ovary cells has a dramatic effect on their morphology and growth properties. We now report that this effect is due at least in part to the ability of decorin to bind transforming growth factor-beta, an autocrine factor that stimulates the growth of Chinese hamster ovary cells. As transforming growth factor-beta induces synthesis of decorin in many cell types, our results suggest that decorin may be a component of a feedback system regulating cell growth.

Animals↗
PubMed1990

Cerebral cortical calbindin D28K and parvalbumin neurones in Down's syndrome.

Anti-calbindin D28K (CaBP) and anti-parvalbumin (PVA) antibodies were used to study the number and size of neurones containing these two calcium binding proteins in post-mortem brains from 7 neurologically normal controls and from 4 elderly patients with clinically diagnosed Down's syndrome (DS) and whose brains contained numerous senile plaques and neurofibrillary tangles. The possible co-existence of these two calcium binding proteins in human cerebral cortex was also examined. In the controls, CaBP immunoreactive neurones were mainly non-pyramidal neurones although some pyramidal neurones were also CaBP immunoreactive. All the PVA immunoreactive neurones were non-pyramidal cells. CaBP and PVA did not apparently co-exist with each other in cortical neurones. When compared with the neurologically normal controls, the number and size of CaBP and PVA immunoreactive neurones were significantly reduced in the cortex of patients with DS. These findings show that CaBP and PVA containing cortical neurones are affected in elderly persons with DS.

Aged↗
PubMed1990

Phosphorylation of Tau proteins: a major event during the process of neurofibrillary degeneration. A comparative study between Alzheimer's disease and Down's syndrome.

Six different brain areas from 6 patients with Down's syndrome (DS) of different ages were studied in respect of their Tau protein content using the western-blot technique. They were also studied histologically using a Palmgren (silver staining) method in order to reveal the presence of NFT and SP. The results of these studies show that Tau 64 and 69, two pathological Tau variants recently described in the brains of patients with Alzheimer's disease (AD), are also present in the brains of patients with DS. Alkaline phosphatase treatment demonstrates that their heavy molecular weight is due, as in AD, to an abnormal phosphorylation of Tau proteins. The results of this study show that the detection of Tau 64 and 69 in the brain of these patients is correlated with the presence of neurofibrillary tangles (NFT) and senile plaques (SP). These findings confirm that DS can act as a model for the study of the pathological events that occur in AD. Moreover, they suggest that the abnormal phosphorylation of Tau proteins, enhancing a shift of their electrophoretic mobility, might be an important step among the sequence of events that characterize neurofibrillary degeneration.

Adult↗
PubMed1990

Analysis of glycosaminoglycan substitution in decorin by site-directed mutagenesis.

Posttranslational glycosaminoglycan attachment to decorin, a chondroitin/dermatan sulfate proteoglycan, was studied by expression of a wild-type decorin cDNA and several mutagenized forms in two types of mammalian cells. Transfection of the wild-type cDNA resulted in the synthesis of an authentic chondroitin/dermatan sulfate proteoglycan similar to the decorin molecule synthesized by cultured human fibroblasts. Conversion of the serine residue that serves as the attachment site for the sole glycosaminoglycan chain in decorin to a threonine residue greatly reduced the efficiency of the glycosaminoglycan substitution. Less than 10% of the threonine-mutated core protein acquired a glycosaminoglycan chain, whereas most of the core protein was secreted without such substitution. Expression of cDNA in which an alanine residue had been introduced into the substituted serine position resulted in the secretion of core protein with no detectable glycosaminoglycan. Conversion to alanine of either one of the glycine residues that are adjacent to the substituted serine yielded the proteoglycan form of decorin. These results show that the xylosyltransferase responsible for the initiation of the glycosaminoglycan chain on the core protein can use a threonine residue for this substitution instead of a serine residue, but that such substitution is only partial, creating a "part-time" proteoglycan. Moreover, variations are possible in the sequence context of a glycosaminoglycan-substituted serine residue without loss of glycosaminoglycan substitution. The conformation of the substitution site may therefore be important for xylosyltransferase recognition.

Animals↗
PubMed1990

Deposition of amyloid (A4) protein within the brains of persons with dementing disorders other than Alzheimer's disease and Down's syndrome.

Deposition of amyloid (A4) protein was assessed in the cerebral cortex of 26 patients dying with various neurodegenerative disorders, other than Alzheimer's disease. Amyloid deposits were (variably) present in 2/3 (66%) elderly (i.e. over 65 years of age) patients with progressive supranuclear palsy, 4/7 (57%) with Parkinson's disease, 2/5 (40%) with Huntington's chorea and in both elderly patients with frontal lobe dementia but were only rarely seen in any patient before this age. The A4 protein deposits were nearly always of a diffuse type with only an occasional 'cored' neuritic plaque being present. Amyloid deposition in elderly persons may thus relate more to certain aspects of ageing and genetics than to AD, per se. Only in this latter condition are the cerebral cortical amyloid deposits widely associated with a neuritic change and a neurofibrillary degeneration of nerve cells.

Adult↗
PubMed1990

The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease.

The extent of amyloid deposition within the cerebellum and the cerebral cortex was assessed and compared, using anti-amyloid protein (A4) immunostaining and a novel methenamine silver method, in 20 patients aged between 60 and 77 years with Alzheimer's disease (AD), 29 patients aged between 13 and 71 years with Down's syndrome (DS), 26 demented patients with disorders other than AD and DS and in 20 non-demented elderly individuals of age range 60-102 years. In AD, amyloid deposits were noted in the cerebellar cortex in 90% of patients and in the meningeal vessels of the cerebellum in 80% of patients. In DS, amyloid deposits were seen in the cerebellar cortex in 82% of patients over 30 years of age and was universal in patients over 50 years of age. Overall, in DS, amyloid deposits were present in the meningeal vessels of the cerebellum in 79% of patients, but were present in 94% of those patients over 50 years of age. The sites of amyloid deposition in the cerebellar cortex were (poorly) detected by lectin histochemistry (Concanavalin A binding) in only 40% of patients with AD and 43% of all patients with DS (69% of those over 50 years of age). No amyloid deposits were seen in either the cerebellar cortex or its meningeal vessels in any of the 20 non-demented elderly individuals nor in any of the non-Alzheimer demented patients. The cerebellar amyloid deposits were never associated with a neuritic change [i.e. as characterised by the presence of (tau-positive) paired helical filaments (PHF)] and neurofibrillary tangles were seen only in a few cells of the dentate nucleus in a single patient with AD and in three of the elderly DS patients. Amyloid deposits were numerous in the cerebral cortex of all patients with AD and in all, except the 13-year-old patient, with DS. In all the AD patients and in most of the DS patients over 30 years of age, many of the cerebral cortical amyloid deposits were associated with neurites and were strongly recognised by lectin histochemistry. Amyloid deposits were present within the meningeal vessels of the cerebral cortex in 75% patients with AD and 72% of patients, over 30 years of age, with DS (82% of those over 50 years of age). These data indicate that the process of amyloidosis in AD and in elderly DS patients is not restricted to the cerebral cortex and may affect other grey matter regions, particularly the cerebellum.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

A quantitative assessment of somatostatin-like and neuropeptide Y-like immunostained cells in the frontal and temporal cortex of patients with Alzheimer's disease.

Immunocytochemical studies utilizing radioimmunoassay and morphological techniques have provided conflicting evidence for the involvement of somatostatin and neuropeptide Y in Alzheimer's disease (AD). However, previous investigators have not considered the effects of cortical atrophy in AD tissue on their findings. This study reports the numbers of somatostatin-like (SLI) and neuropeptide Y-like immunoreactive (NPYLI) neuronal perikarya and the length of SLI and NPYLI immunoreactive fibres, with appropriate corrections for atrophy in 6 control and 6 AD cases. There were significantly fewer SLI neurones in AD in layers II + III combined from the temporal cortex, and fewer NPYLI neurones in layers V + VI in both frontal and temporal cortices. Using a randomized method to quantify immunostained fibre length in the neuropil, an analysis of variance revealed no significant differences in the mean SLI or NPYLI fibre length per cortical strip between control and AD groups in frontal or temporal cortex. However, using a second measure of fibre length by tracing the fibres attached to consecutive immunostained perikarya, there were significant reductions in the AD brains in the mean fibre length per cell in layers V + VI for SLI in the temporal cortex, and for NPYLI in the frontal cortex. This reduction in fibre length per individual cell was presumably masked by the large variation in the fibre length found between cases using the randomized approach. It was concluded that in order to evaluate the involvement of these neuropeptides in AD from any measurements of concentration, it is essential to include some compensation for the extent of cortical atrophy that occurs with the disease.

Aged↗
PubMed1990

Some morphometric observations on the brains of patients with Down's syndrome: their relationship to age and dementia.

The number of senile plaques (SP) and neurofibrillary tangles (NFT) and the number and nucleolar volume of nerve cells have been estimated in certain cortical and subcortical regions in 22 patients with Down's syndrome (DS) and have been related to the patients' age and to the presence and severity of dementia. Elderly (i.e. over 50 years of age) patients showed increased densities of SP and NFT and significant reductions in number and nucleolar volume of nerve cells, when compared with patients under 50 years of age, though the extent of these changes was, in general, no greater in the non-demented elderly group than that in the demented elderly group. Of the younger, nondemented group, those patients with a limited formation of SP and NFT in their brains showed a similar number and nucleolar volume of nerve cells, as those completely devoid of SP and NFT. It is concluded that in DS, formation of SP and NFT predate any significant atrophy and loss of nerve cells and that it is only after the age of 50 years that gross atrophy and loss of neurones occurs, though the extent of this process seemingly does not predict the onset, nor the progress, of dementia.

Adolescent↗
PubMed1990

A morphological analysis of senile plaques in the brains of non-demented persons of different ages using silver, immunocytochemical and lectin histochemical staining techniques.

The prevalence and severity of senile plaque (SP) formation was investigated in the cerebral cortex, hippocampus and amygdala of 60 non-demented individuals of age range 6-84 years, using immunocytochemical (anti-A4 amyloid, anti-PHF protein), lectin histochemical (Con A binding) and silver (Methenamine (MS) and Palmgren), staining methods. By at least one of these methods, 18 patients showed the presence of SP within one or more of these brain regions; 15 of these patients were over 60 years of age. Comparisons between each staining method showed that, in the hippocampus and amygdala all five methods detected the presence and number of SP equally well, whereas, in the cerebral cortex, MS and anti-A4 staining demonstrated more SP in a greater number of patients than did either Con A or Palmgren silver and anti-PHF staining. The additional SP detected by these former two staining methods contained diffuse deposits of amyloid (A4) protein, and sometimes also large clumps of Con A positive material, but no neurites as detected by Palmgren or anti-PHF staining. Such SP closely resemble those seen in the cerebral cortex of young patients with Down's syndrome, and which are thought to be an early form of SP. The relationship between the pathological changes in these non-demented patients and a possible diagnosis of early Alzheimer's disease is discussed.

Adolescent↗
PubMed1990

Frontal lobe dementia and motor neuron disease.

Four patients are described, in whom a profound and rapidly progressive dementia occurred in association with clinical features of motor neuron disease. The pattern of dementia indicated impaired frontal lobe function, confirmed by reduced tracer uptake in the frontal lobes on single photon emission computed tomography (SPECT). Pathological examination of the brains of two patients revealed frontal-lobe atrophy, with mild gliosis and spongiform change. The spinal cord changes were consistent with motor neuron disease. The clinical picture and pathological findings resembled those of dementia of frontal-lobe type and were distinct from those of Alzheimer's disease. The findings have implications for the understanding of the spectrum of non-Alzheimer forms of primary degenerative dementia.

Adult↗
PubMed1989

Reduced D-[3H]aspartate binding in Down's syndrome brains.

The binding of D-[3H]aspartate to glutamate uptake sites was measured in post-mortem brains from subjects with Down's syndrome (DS) and age-matched controls. DS brains had substantially reduced D-[3H]aspartate binding in the frontal and temporal cortex, hippocampus and caudate nucleus. There was no correlation between the numbers of Alzheimer-like plaques and tangles or clinically-assessed dementia and D-[3H]aspartate binding in DS brains. The binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine ([3H]TCP) to postsynaptic N-methyl-D-aspartate sites was normal in DS brains. This study suggests that the reduction in glutamate uptake sites in DS is more substantial and widespread than in Alzheimer's disease.

Aged↗
PubMed1989

Topographical mapping of calmodulin-target enzyme interaction domains.

Calmodulin derivatives, specifically biotinylated in domains I and III, were synthesized to address the structures of calmodulin necessary for binding to its target enzymes in active conformations. By binding avidin to these biotinylated calmodulins, the role of specific sequences of the calmodulin molecule in target enzyme interactions could then be evaluated. The role of domain I in these interactions was assessed by biotinylation of Cys-27 of wheat germ calmodulin with N-ethylmaleimidobiotin. This modification did not affect the ability of this calmodulin to activate 3'-5'-cyclic nucleotide phosphodiesterase (PDE) or human erythrocyte Ca2+-Mg2+ ATPase. The addition of avidin to form a stable calmodulin-avidin complex also did not affect activation. Bovine testes calmodulin was biotinylated on Lys-94 by calcium-dependent reaction with N-hydroxysuccinimido ester-biotin at pH 6.0. This derivative was used to probe the Ca+2 binding region of domain III. The incorporation of biotin at Lys-94 of bovine calmodulin did not affect calmodulin activation of PDE. However, compared to unmodified calmodulin, a 4-fold higher concentration of this derivative was required to fully activate the ATPase. The addition of excess avidin to this derivative abolished all activation for both PDE and the ATPase. Sites of modification were determined by sequence analysis of labeled peptides.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1989

Effects of modifications of the RGD sequence and its context on recognition by the fibronectin receptor.

The receptor for fibronectin is a member of the integrin superfamily of cell surface adhesion receptors, many of which recognize the sequence RGD in their ligands. We have developed sensitive enzyme-linked and radioreceptor assays to examine the ligand specificity of the fibronectin receptor. The fibronectin receptor bound only to fibronectin of the various Arg-Gly-Asp (RGD)-containing proteins tested. The smallest amount of receptor detectable in the assay was about 10 ng. Mn2+ enhanced the binding of the receptor to fibronectin 3-10-fold as compared to Ca2+ and Mg2+. Scatchard analysis of the saturation plot from the radioreceptor assay gave a dissociation constant (Kd) of 3 x 10(-8) M for the binding of fibronectin receptor to fibronectin in the presence of Mn2+. Inhibition experiments showed that the affinities of the ligands for the receptor decreased in the order of fibronectin approximately 110-kDa fibronectin fragment greater than GRGDSP peptide greater than 11.5-kDa fragment. Peptides not containing an RGD were several hundred to several thousand-fold less inhibitory than GRGDSP. These included the closely related peptides GRADSP and GRGESP, as well as three peptides containing the reverse sequence DGR. A peptide from the fibrinogen gamma-chain, KQAGDV, which had about 0.5% of the inhibitory activity of the standard GRGDSP peptide, was the most active peptide not containing an RGD. These results document the exquisite specificity of the fibronectin receptor for the RGD sequence.

Calcium↗
PubMed1989

Regulation of collagenase and collagenase mRNA production in early- and late-passage human diploid fibroblasts.

The levels of collagenase and collagenase mRNA produced by early-passage (less than 40% of lifespan completed) and late-passage (greater than 80% of lifespan completed) cultures of human fibroblasts were analyzed. The constitutive levels of collagenase and collagenase mRNA produced by the late-passage cultures were 10-30 x greater than the levels observed in similarly treated early-passage cultures. Immunofluorescence analysis established that the percentage of collagenase-positive cells was also greater (77% vs. 4%) in the late-passage cultures. To determine whether the difference in collagenase production resulted from cell-derived regulatory factors, collagenase production was examined in cultures plated onto substrates coated with fibroblast extracellular matrix (ECM). Collagenase and collagenase mRNA production was enhanced in both types of cultures, although amounts produced by ECM-induced early-passage cultures was significantly less than that produced by similarly treated late-passage cultures. Collagen-coated substrates also induced collagenase synthesis.

Cells, Cultured↗
PubMed1989

Subcortical afferent projection systems in Huntington's chorea.

The number and nucleolar volume of nerve cells within the nucleus basalis of Meynert, locus caeruleus, substantia nigra and dorsal raphe were examined in five patients with Huntington's chorea. No significant changes in nerve cell number were noted in any area in any patient and, although nucleolar volume was reduced in nerve cells of locus caeruleus and substantia nigra in four patients, this was considered to reflect medication rather than to be related to the disease process itself. It is concluded that the subcortical afferent projection systems of the mid-brain and brain stem are unaffected in Huntington's chorea and that the dementia in such patients most likely relates to changes within the cerebral cortex and/or damage to corticopetal pathways within the basal ganglia.

Afferent Pathways↗
PubMed1989

The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome.

The form and distribution of senile plaques (SP) and neurofibrillary tangles (NFT) has been examined in the brains of 13 patients with Down's syndrome (DS), aged less than or equal to 50 years, using immunocytochemical and silver staining procedures. SP become present within the brain before NFT and these appear firstly as fine, even, diffuse areas of anti-amyloid (A4) protein immunoreactivity in the absence of any discernable neuritic change. Later the amount of anti-A4 protein in SP increases and SP show a marked surrounding neuritic response which is detectable using either silver or anti-paired helical filament (PHF) staining methods. At this stage NFT also become detectable within the perikaryon of nerve cells in both the cortex and the subcortex, with the large stellate neurones of layer II of the entorhinal cortex showing an early involvement. By the age of 50 years, most patients are well on the way towards achieving (and some have already achieved) that pattern of SP and NFT morphology and distribution that is typically seen in patients over 50 years of age with DS and in other patients in the general population with Alzheimer's disease.

Adult↗