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Biomedical subjects

D M Mann

Publications and source records attributed to D M Mann.

At least 55 records · Page 3Linked to original sources
PubMed1997

An intronic polymorphism in the presenilin-1 gene does not influence the amount or molecular form of the amyloid beta protein deposited in Alzheimer's disease.

The frequency of the allele-1 polymorphism in intron 8 of the presenilin-1 (PS-1) gene, and the proportion of individuals homozygous in this respect, was investigated in 57 patients with autopsy verified Alzheimer's disease (AD). In 33 of these patients the amount of amyloid beta protein (A beta) was compared across the three PS-1 genotype groups (1/1, 1/2, 2/2). No excess of the allele-1 was detected in these patients with confirmed AD and no variations in the extent of A beta deposition, as either A beta 40 or A beta 42, in terms of plaque number or percentage area of tissue occupied, were found. We conclude that this intronic PS-1 polymorphism does not influence the pathological phenotype of AD, at least as far as A beta deposition is concerned.

Aged↗
PubMed1997

Preferential deposition of amyloid beta protein (Abeta) in the form Abeta40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele.

The effect of apolipoprotein E (ApoE) genotype on the deposition of amyloid beta protein (Abeta) was examined in 54 patients with Alzheimer's disease. No difference in the amount of Abeta deposited as Abeta42(43) was seen between genotype groups with no, one or two E4 alleles. However, the amount of Abeta40 deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele containing more than twice, and those with two E4 alleles, four times, the amount of Abeta40 in their brains compared to patients without an E4 allele. The increase in total Abeta deposited within the tissue (i.e. Abeta40 plus Abeta42(43) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of Abeta40. These data are consistent with the suggestion that the presence of E4 within pre-existing Abeta42(43) containing plaques may lower the threshold to fibrilization of Abeta40 thereby promoting its subsequent deposition. Thus, although the total amount of Abeta initially deposited in the brain as Abeta42(43) is not affected by the binding of any one particular ApoE isoform this does influence the subsequent maturation of plaques with a greater proportion transforming into Abeta40 containing cored plaques when the E4 isoform is present.

Age of Onset↗
PubMed1997

Amyloid (Abeta) deposition in chromosome 1-linked Alzheimer's disease: the Volga German families.

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 6 cases of (genetically confirmed) chromosome 1-linked Alzheimer's disease (AD) (PS-2 gene mutation) among the Volga German families using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present, although the total amount of Abeta40 and Abeta42(43) deposited in plaques did not differ from that seen in sporadic AD and was significantly lower than that occurring in AD due to PS-1 gene mutations. Therefore, mutations in the PS-2 gene, like those in the presenilin-1 (PS-1) and amyloid precursor protein (APP) genes, are associated with an initial and preferential deposition of Abeta42(43) within the brain. Although the mechanism(s) whereby the PS-1 and PS-2 gene mutations operate remains unclear, it seems from the present study that the effect of the PS-2 gene mutation on the brain is much less severe, at least as far as Abeta deposition is concerned, than that of the PS-1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.

Aged↗
PubMed1997

Monoclonal antibodies to purified cortical Lewy bodies recognize the mid-size neurofilament subunit.

Lewy bodies (LBs) are filamentous intraneuronal inclusions that are hallmark lesions of Parkinson's disease, and LBs have been shown, by immunohistochemistry, to contain cytoskeletal as well as other cellular proteins. Similar LBs also occur in the cortical neurons of a subset of patients with Alzheimer's disease (AD), and cortical LBs are the predominant or sole lesions in the brains of patients with an AD-like dementia known as diffuse Lewy-body disease (DLBD). To gain insight into the biochemical composition of LBs, we generated monoclonal antibodies (mAbs) to LBs purified from the brains of patients with DLBD. Here, we describe three of these new mAbs (LB48, LB202, and LB204) that stained LBs by immunohistochemistry and recognized the medium molecular mass neurofilament (NF) protein in western blots. These results support the hypothesis that NF subunits are integral components of LBs. Continued efforts to clarify the composition of LBs are likely to lead to novel strategies for the antemortem diagnosis of LB disorders as well as to insight into the role LBs play in the degeneration of affected neurons in these disorders.

Antibodies, Monoclonal↗
PubMed1996

Debrisoquine hydroxylase gene polymorphism frequencies in patients with amyotrophic lateral sclerosis.

Using PCR and restriction digest analysis, the frequencies of the variant cytochrome P450 debrisoquine hydroxylase CYP2D6 alleles CYP2D6(A) and CYP2D6(B) were investigated in 50 patients with amyotrophic lateral sclerosis (ALS) and 13 patients with ALS and frontotemporal dementia (FTD) and compared to those frequencies in patients with FTD alone and Alzheimer's disease (AD). The CYP2D6(T) allelic frequency was also assessed in ALS and ALS + FTD. Although the frequency of a poor metabolizer genotype was not increased in any disease group, there was a significant increase in the frequency of the CYP2D6(B) allele in the ALS patient group. This suggests that possession of a CYP2D6(B) allele may be a risk factor for the development of ALS, possibly conferring a 'gain of function' imposed by the mutation or reflecting linkage disequilibrium to a nearby susceptibility gene.

Alleles↗
PubMed1996

Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer's disease: predominance of Abeta42(43).

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 8 cases of (genetically confirmed) chromosome 14-linked Alzheimer's disease (AD) using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present. The total amount of Abeta40 and Abeta42(43) deposited was more than twice the amount deposited in cases of sporadic AD of similar disease duration, although the ratio between the extent of Abeta40 and Abeta42(43) deposition was unaltered, compared with sporadic AD. Therefore, (one of) the effects of the mutations in the presenilin 1:PS-1 (S182) gene may be to cause or at least promote an early and excessive deposition of Abeta42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).

Adult↗
PubMed1996

Serglycin-binding proteins in activated macrophages and platelets.

The major proteoglycan in macrophages and platelets is the chondroitin sulphate proteoglycan serglycin. To study the biological role of serglycin, its binding to secreted and cell-associated proteins from macrophages and blood platelets was examined. Affinity chromatography with serglycin-Sepharose and chondroitin sulphate-Sepharose was used to isolate proteoglycin-binding proteins from macrophages and platelets. Antibodies against human macrophage inflammatory protein-1 alpha (MIP-1 alpha) precipitated a 14-kDa 35S-methionine-labeled protein among the chondroitin sulfate binding proteins secreted from the macrophage-like U937 cells after stimulation. Two proteins from murine macrophage J774 cells with molecular masses of approximately 10 and 14 kDa were precipitated by an antiserum against the murine MIP-1 alpha. Protein sequencing of fragments obtained by trypsin digestion of a 14-kDa chondroitin sulfate-binding protein from cell extracts of stimulated U937 cells revealed 100% homology with lysozyme, a bacteriolytic enzyme. Fragment of one other protein with approximate molecular mass of 8 kDa showed high homology with bone morphogenetic protein. Inhibition studies showed that chondroitin 6-sulfate inhibited the bacteriolytic activity of lysozyme in a competitive manner more efficiently than heparin and chondroitin 4-sulphate. Amino-terminal sequencing of two proteins from platelet extracts that bound to serglycin-Sepharose revealed that they corresponded to multimeric forms of human platelet factor 4 (PE4). Chondroitin sulfate-Sepharose was shown to be equally efficient in retaining PF4 from platelet extracts as serglycin-Sepharose indicating that the glycosaminoglycan chains mediate the binding to PF4 in the intact proteoglycan molecule. Competition experiments showed that serglycin was as efficient as heparin sulfate in blocking the binding of [3H] chondrotin sulfate to PF4, whereas heparin was one order of magnitude more efficient. Affinity measurements using fluoresceinamine-labeled glycosaminoglycans showed that the affinity of heparin for PF4 is on the order of 30 nM, whereas chondroitin sulfate has an affinity of 260 nM. Both PF4, MIP-1 alpha, and lysozyme play important role in different types of inflammatory reactions. The interaction with serglycin may indicate that this proteoglycan is involved in the regulation of the inflammatory response.

Animals↗
PubMed1996

Diffuse plaques in the cerebellum and corpus striatum in Down's syndrome contain amyloid beta protein (A beta) only in the form of A beta 42(43).

The diffuse amyloid (A beta) plaques of the cerebellum and corpus striatum were examined in 32 patients with Down's syndrome, ranging in age from 9 to 71 years, using the end-specific monoclonal antibodies BA27 and BC05 to detect A beta species terminating at amino acids 40 and 42(43) respectively. When present, the diffuse plaques of both regions contained only A beta 42(43) at all ages. A beta 40 was, however, present along with A beta 42(43) in the few cored plaques that were occasionally present in the Purkinje and molecular cell layers of the cerebellum of some of the more elderly patients. It is concluded that diffuse plaques of the cerebellum and striatum contain only A beta 42(43) and that, in contrast to those of the cerebral cortex, these do not "mature' during their lifetime into A beta 40 containing plaques.

Adolescent↗
PubMed1996

Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease.

The expression of the presenilin 1 (PS-1) gene has been investigated by in situ hybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14-linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situ hybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS-1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5' end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.

Adult↗
PubMed1996

Pyramidal nerve cell loss in Alzheimer's disease.

Loss of the large pyramidal cells of the association neocortex and hippocampus, along with plaques and tangles, is fundamental to the neuropathology of Alzheimer's disease. The extent of Alzheimer-specific cell loss, relative to controls, is age-dependent with maximal losses in younger subjects though, because of the (additive) effects of 'normal' ageing on such cells, the absolute loss remains constant at all ages. The cause of the cell loss remains unknown but probably relates to neurofibrillary degeneration through a crowding out of organelles and a disruption of intracellular transport; oxidative stress may also contribute. The degree of clinical dementia correlates well with the extent of pyramidal cell loss.

Alzheimer Disease↗
PubMed1996

Atypical amyloid (A beta) deposition in the cerebellum in Alzheimer's disease: an immunohistochemical study using end-specific A beta monoclonal antibodies.

We have used the end-specific monoclonal antibodies to amyloid beta-protein (A beta), BC05 and BA27, to investigate the molecular characteristics of the cored or stellate type of amyloid plaque that is sometimes present, along with the more common diffuse type of plaque, in the cerebellar cortex in (usually younger) cases of Alzheimer's disease. In five such cases of Alzheimer's disease the (many) cored plaques were strongly BA27, but less strongly BC05, immunopositive, indicating the presence of (much) A beta 40 and A beta 42(43), respectively. Diffuse plaques were only BC05 positive, except on rare occasions where a litter BA27 reactivity was present. Cerebellar cored plaques, like the diffuse plaques, were not associated with tau or astrocytic (glial fibrillary acid protein) immunoreactivity, though in contrast to cerebellar diffuse plaques, but like the cored plaques in the cerebral cortex, microglial cells were usually present. The cause of this form of A beta deposition in the cerebellum is not known. Although congophilic angiopathy was severe in two patients, this was only mild in the other. Similar plaques were also seen in the cerebellum of most, but not all, of five other younger patients with chromosome 14-linked Alzheimer's disease and again, although congophilic angiopathy was severe in one such case with many cored plaques, this was not so in the others. At present the relationship (if any) between this pathological change and the possession of the chromosome 14 mutation of Alzheimer's disease or the occurrence of congophilic angiopathy remains uncertain.

Adult↗
PubMed1996

Transvenous procurement of pulmonary artery smooth muscle and endothelial cells using a novel endoarterial biopsy catheter in a canine model.

OBJECTIVES: The aim of this study was to evaluate the performance of a new arterial biopsy catheter in obtaining pulmonary endovascular samples in a canine model. BACKGROUND: Percutaneous endomyocardial biopsy is a widely used and valuable procedure in the management of posttransplant rejection and selected cardiomyopathies. A similar method of obtaining endoarterial biopsy samples would aid in the study, diagnosis and management of arterial diseases. METHODS: Catheterization was performed in 19 dogs, each weighing 20 to 30 kg, through an 8F sheath in the external jugular vein to obtain pulmonary endoarterial samples. The catheter consists of two sliding tubes: an inner one with a beveled opening that accommodates endoarterial tissue by means of a vacuum and an outer tube with a sharp distal edge that cuts the tissue when activated. RESULTS: Overall, a total of 266 separate biopsy attempts were performed, and 161 tissue samples were obtained (success rate 61%). With modifications in technique in the last nine dogs, 54 (93%) of 58 attempts were successful. There were no deaths, extravasation of contrast material on angiography or thrombi. Of 20 vessels with prebiopsy and postbiopsy angiograms, 1 developed transient spasm (5%). On microscopic examination of cross sections of 50 separate pulmonary endoarterial biopsy samples, all had smooth muscle cells and 30 contained endothelial cells (60%). The arteries of origin showed small intimal and medial tears and mild perivascular hemorrhage. Angiographic and pathologic examination of previously biopsied arterial segments 2 weeks (two dogs) and 8 weeks (two dogs) after the procedure showed patent vessels and no thrombi. Histologically, the biopsy sites revealed mild neointimal and medial proliferation. CONCLUSIONS: This new endoarterial biopsy catheter is safe and effective in obtaining pulmonary artery samples in normotensive dogs.

Angiography↗
PubMed1996

Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome.

Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.

Adolescent↗
PubMed1996

Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the cerebellum and striatum in Alzheimer's disease and Down's syndrome.

The lysosomal hydrolases, cathepsin D (Cat D) and beta-hexosaminidase A (HEX), which are normally intracellular enzymes, colocalize with beta-amyloid in a subgroup of diffuse plaques in the cerebellum and striatum of individuals with Alzheimer's disease or Down's syndrome. Using specific antisera in combination with single- and double-label immunocytochemical techniques, extracellular hydrolase was detected in 30 to 40% of the diffuse plaques in the cerebellar molecular layer and nearly all of the diffuse plaques in the striatum. In both Alzheimer's disease and Down's syndrome, about 5 to 10% of the cerebellar Purkinje cells contained abnormally increased numbers of hydrolase-positive lysosomes despite their normal appearance by conventional histologic stains. Occasional atrophic Purkinje cells identified by Nissl stain were intensely immunostained. By confocal imaging analysis, abnormal hydrolase-laden Purkinje cell dendrites were seen coursing through some hydrolase-positive plaques and were continuous with dendritic branches that terminated within deposits of extracellular hydrolase and beta-amyloid. In the striatum, intensely immunostained abnormal-appearing neurons were commonly associated with extracellular deposits of hydrolase immunoreactivity and beta-amyloid within diffuse plaques and in the less commonly seen classical plaques. In both brain regions, other hydrolase-negative beta-amyloid deposits were seen, these being associated with blood vessels. The presence of HEX immunoreactivity in neurons, but not in glia, and its abundance in plaques support earlier studies, suggesting that neurons are the principal source of plaque hydrolase. An endosomal-lysosomal system upregulation, with increased hydrolase expression and extracellular enzyme deposition in plaques, is, like beta-amyloid deposition, an early marker of metabolic dysfunction potentially related to primary etiologic events in Alzheimer's disease and Down's syndrome.

Adult↗
PubMed1996

Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene.

Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in the amyloid precursor protein (APP) gene using the end-specific monoclonal antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively. In cases of APP717 mutation the predominant A beta species within plaques terminate at A beta 42(43) with relatively little A beta 40 being present. The total amount of A beta deposited as A beta 42(43) is significantly greater than in sporadic Alzheimer's disease, consistent with the suggestion that this mutation might influence the processing of APP so as to produce more of the highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major peptide in plaques is also A beta 42(43), although the proportion of plaques containing A beta 40, and the total A beta load is similar to that in sporadic Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder, however, parenchymal deposits are exclusively A beta 42(43). Although the various APP mutations may influence the type, quantity, and location of A beta deposited, the predominant, and possibly the initial, species deposited in the brain parenchyma is A beta 42(43).

Adult↗
PubMed1996

Patterns of glial cell activity in fronto-temporal dementia (lobar atrophy).

Fronto-temporal dementia is a clinical syndrome with a number of pathological substrates, including frontal lobe degeneration, Pick's disease, and motor neuron disease with dementia; it also includes patients with a primary progressive language disorder. Twenty-four brains were examined, using immunohistochemistry for glial fibrillary acidic protein (GFAP) and ferritin. Five cases of fronto-temporal dementia with a Pick's disease type of histology showed marked cortical gliosis with striking microglial activity in both grey and white matter. In seven cases of frontal lobe degeneration, there was little gliosis and microglial activity was confined largely to the white matter; two of the seven cases of progressive language disorder showed similar changes to frontal lobe degeneration. Five cases of motor neuron disease with dementia showed both astrocytic and microglial activity within the white matter. We suggest that cases of fronto-temporal dementia due to Pick type histology may result from a process which primarily involves grey matter, whereas cases of frontal lobe degeneration might represent a disorder of white matter.

Astrocytes↗