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D M Mann

Publications and source records attributed to D M Mann.

At least 73 records · Page 4Linked to original sources
PubMed1996

Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques.

The amino- and carboxyl-terminal properties of the amyloid-beta (A beta) peptides deposited in diffuse plaques, one of the earliest forms of A beta deposition, were examined in the brains of patients with Down's syndrome and Alzheimer's disease and in aged individuals without dementia by immunocytochemistry. This was done using a panel of antibodies that specifically discriminate the terminal structures and modifications at the amino and carboxyl termini of A beta. Diffuse plaques found in the cerebral and cerebellar cortex, neostriatum, and hypothalamus of Down's syndrome, Alzheimer's disease, and nondemented brains were strongly immunoreactive for A beta N1(L-Asp), A beta N1(L-isoAsp), A beta N1(D-Asp), and A beta N3(pyroGlu) and weakly positive for A beta N11(pyroGlu) and A beta N17(Leu). Diffuse plaques also were positive for A beta 42(43) but negative for A beta 40, using carboxyl-terminal-specific anti-A beta antibodies. These results suggest that the amino termini of the A beta species that initially deposit in diffuse plaques begin with A beta N1(Asp) with or without structural modifications (isomerization and racemization), as well as with A beta N3(pyroGlu), and terminate preferentially at A beta 42(43) rather than A beta 40.

Adult↗
PubMed1995

The extent of amyloid deposition in brain in patients with Down's syndrome does not depend upon the apolipoprotein E genotype.

The extent of deposition of amyloid beta protein (A beta) was investigated in 20 elderly patients with Down's syndrome, using the end-specific monoclonal antibodies BC05 and BA27 to detect the presence of A beta 42(43) and A beta 40 (respectively), and related to apolipoprotein E (ApoE) genotype. No significant differences in the amount of A beta deposited in the brain, either as A beta 42(43) or A beta 40, were noted in patients possessing an ApoE E4 allele, compared to those without. Patients with an ApoE E4 allele in general died at an earlier age than those with only ApoE E3 alleles, the latter in turn being outlived by those with an ApoE E2 allele. In Down's syndrome therefore, ApoE may influence the timing of onset, or the rate of progression, of disease but without affecting the type or total amount of pathology accumulated.

Aged↗
PubMed1995

Locus coeruleus cell loss in the aging human brain: a non-random process.

Quantitative neuroanatomical techniques were used to determine whether with aging there is random or systematic loss of locus coeruleus (LC) neurons in the human brain. The cells were identified by immunohistochemical staining for the catecholaminergic enzyme tyrosine hydroxylase and/or by neuromelanin pigment content. Cell locations were mapped, using computer imaging procedures, in horizontal sections spaced 0.5 to 0.8 mm throughout the rostrocaudal extent of the nucleus in 17 cases, from 1 to 104 years of age. Neuromelanin pigment accumulated within the neurons with aging. In brains less than 25 years of age there were many fewer pigment-containing neurons than tyrosine hydroxylase-containing neurons; however, by the fifth decade the number of cells identified by the two markers was comparable. From the first to the tenth decade of life there is over a 50% loss of LC neurons: in four cases from "young" individuals (1-28 years of age) there were 21,084 +/- 653 tyrosine hydroxylase immunostained cells (mean +/- standard error of the mean) on one side of the brain; in seven cases from "old" individuals (60-82 years of age) there were 16,502 +/- 921 pigment-containing cells; and in the three cases from the "oldest" individuals (103-104 years of age) there were 9,493 +/- 1,236 pigment-containing neurons. In both the "old" and "oldest" groups, compared to the "young," there was significantly greater loss of rostral cells than caudal cells. These data indicate a systematic loss of cells such that the rostral, forebrain-projecting neurons decrease in number with aging to a greater extent than do the caudal, spinal cord-projecting neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling.

Cultured aortic smooth muscle cells (SMC) exhibit morphological and phenotypic modulation characterized by a change from a substrate attached monolayer culture to a multilayered nodular cell culture in which SMC are imbedded into the extracellular matrix. Associated with nodule formation is a change in the pattern of SMC gene expression including increased expression of a well characterized marker of smooth muscle cell differentiation, SM alpha-actin, and a 38-kDa glycoprotein (gp38k). gp38k has sequence homology with proteins reported to be correlated with tissue remodeling. To characterize the gp38k mRNA we designed degenerate oligonucleotides based on partial polypeptide sequencing to select a cDNA encoding the full-length gp38k. Southern analysis indicates that porcine gp38k is present as a single copy gene. Northern analysis indicates that the increase in gp38k is correlated with an increase in the steady state level of gp38k mRNA; and is present in cultures that have initiated the formation of multilayered foci and nodules. The correlation between SMC differentiation and gp38k expression is further established by using culture conditions that facilitate SMC differentiation. Cultures seeded onto reconstituted extracellular matrix show rapid formation of nodules and increased expression of gp38k mRNA. Comparison of the gp38k and cDNA sequences with nucleotide and protein sequences available through GenBank and SwissProt data banks revealed that molecules homologous to gp38k were present in human, mouse, bovine, and Drosophila tissues, suggesting that the gp38k may be a member of a gene family. Although a function for gp38k has not been identified, this report represents the first report of its correlation with a specific process important in phenotypic and morphological modulation of vascular SMC.

Adipokines↗
PubMed1995

Apolipoprotein E allelic frequencies in patients with lobar atrophy.

Apolipoprotein E (ApoE) genotype was determined by polymerase chain reaction amplification and restriction digestion of DNA extracted from brain tissues of 26 patients with clinically diagnosed and pathologically verified lobar atrophy (LA) and from blood of a further 22 patients with clinical LA. Brain tissue from 50 patients with pathologically confirmed Alzheimer's disease (AD) was also examined. As has been previously reported, the ApoE E4 allele frequency was significantly increased in AD. However, no change in the frequency of ApoE alleles was found in two of the clinical and pathological forms of LA (dementia of frontal type and dementia of frontal type with motor neurone disease) although the ApoE E4 allele frequency was elevated in cases of non-fluent progressive aphasia in accordance with the presence of coincidental Alzheimer-type pathological changes.

Aged↗
PubMed1995

Allelic variations in apolipoprotein E and prion protein genotype related to plaque formation and age of onset in sporadic Creutzfeldt-Jakob disease.

Prion gene sequence is thought to affect the phenotypic expression of prion disease and the E2 variant of apolipoprotein E (Apo E) can be neuroprotective in dementia. We determined codon 129 of the prion gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR and restriction digest. We found a significant correlation between valine at codon 129 of the prion protein gene and the presence of plaque in CJD and a later age of onset in CJD cases possessing the Apo E2 allele. This study provides further evidence that sequence variations in the prion gene can modify disease pathology and the neuroprotection afforded by Apo E2 is not confined to Alzheimer's disease.

Age of Onset↗
PubMed1995

Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype.

BACKGROUND: The neuropathological changes of Alzheimer's disease occur universally in individuals with Down's syndrome as they reach middle age and worsen with increasing age. Thus, evaluation of patients of various ages with Down's syndrome allows one to construct a life history of the development of neuropathological changes associated with Alzheimer's disease at various points in the disease process. METHODS: We have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and A beta amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with Down's syndrome ranging in age from 4 to 73 years. RESULTS: Neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields, affecting the entorhinal cortex, area CA1/subiculum, then other hippocampal subfields. Although amyloid deposition occurs more evenly in a more widespread distribution, it also accumulates over the years 30 to 50. Surprisingly, examination of the patients available older than 50 years showed no trend toward continued increased deposition of amyloid. Within this group, however, individuals who had inherited the apolipoprotein E (Apo E) epsilon 4 genotype contained more than twice the amyloid burden of individuals who did not inherit the Apo E epsilon 4 genotype. COMMENT: This large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and CA1/subiculum for neurofibrillary tangles and a more widespread but specific topography of A beta deposition. Moreover, it demonstrates quantitatively that the lesions increase to a certain level and then apparently reach a plateau. The level of amyloid deposition in Down's syndrome is higher than in sporadic Alzheimer's disease. Inheritance of the Apo E epsilon 4 genotype appears to be an additional (independent) risk factor for developing higher levels of amyloid accumulation.

Adolescent↗
PubMed1995

Tau, ubiquitin, and alpha B-crystallin immunohistochemistry define the principal causes of degenerative frontotemporal dementia.

OBJECTIVE: We investigated the use of immunostaining with antibodies to tau, ubiquitin, and alpha B-crystallin in defining a protocol for the staged neuropathologic examination of brains from patients with a progressive frontotemporal dementia. DESIGN: Brains obtained from 50 patients dying with the clinical diagnosis of frontotemporal dementia were examined histopathologically to define pathologic distinctions. SETTING: Two university hospital neuropathology departments. RESULTS: Anti-tau immunostaining defined corticobasal degeneration, Alzheimer's disease, and Pick's disease; antiubiquitin defined motor neuron disease with dementia. The remaining brains have frontal lobe degeneration: the use of alpha B-crystallin immunostaining, on these, to detect ballooned neurons may help to define two groups of patients, one of which we believe may represent a variant of Pick's disease. CONCLUSION: These findings indicate that immunostaining with these antibodies is essential for the evaluation of frontal dementia.

Antibodies↗
PubMed1995

Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome.

The chronological relationship regarding deposition of amyloid beta protein (A beta) species, A beta 40 and A beta 42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years. The frontal cortex was probed with two end-specific monoclonals that recognize A beta 40 or A beta 42(43). All senile plaques detected with an authentic beta monoclonal were also A beta 42(43) positive, but only a varying proportion was A beta 40 positive. In young (< or = 50 years old) brains there were many A beta 42(43)-positive, A beta 40-negative diffuse plaques, but only few A beta 40-positive senile plaques (mean, 6.3% of total number of senile plaques). The 2 youngest Down syndrome brains showed only diffuse plaques that were all A beta 42(43) positive but A beta 40 negative. Old (> 50 years old) brains contained many mature senile plaques with amyloid cores in addition to diffuse and immature plaques and the proportion of A beta 40-positive senile plaques was increased (mean, 42% of total). Cerebral amyloid angiopathy was more abundant in old Down syndrome brains and was positive for both A beta 40 and A beta 42(43). In cerebral amyloid angiopathy, A beta 40 predominated over A beta 42(43) in both staining intensity and number of positive vessels. These results indicate that (1) the A beta species initially deposited in the brain as senile plaques is A beta 42(43) and A beta 40 only appears a decade later, and (2) in cerebral amyloid angiopathy A beta 40 appears as early as A beta 42(43).

Adult↗
PubMed1995

Microglial cells and amyloid beta protein (A beta) deposition; association with A beta 40-containing plaques.

Two distinct species of amyloid beta protein (A beta) with different carboxyl termini, A beta 40 and A beta 42(43), are deposited in plaques in the brains of patients with Alzheimer's disease and Down's syndrome. The relationship between these two forms of A beta and microglial cells was investigated in 16 subjects with Down's syndrome ranging in age from 31 to 64 years. The amount of A beta 40 in plaques was low in persons under 50 years of age, even though high amounts of A beta 42(43) were present. Microglia were observed most commonly in plaques containing both A beta 40 and A beta 42(43) but less commonly in those with A beta 42(43) alone. The presence of microglial cells in plaques may be associated with the accumulation of A beta 40 and these cells may have a role in the production or processing of this particular molecular species.

Adult↗
PubMed1995

The topographic distribution of brain atrophy in cortical Lewy body disease: comparison with Alzheimer's disease.

The topographic distribution of brain atrophy was quantified by image analysis of fixed coronal brain slices from four patients dying with cortical Lewy body disease (CLBD) all with Alzheimer-type pathology and compared to that in four other patients of similar age and gender dying with Alzheimer's disease (AD) alone. The pattern of atrophy in CLBD (+AD) was broadly similar to that in AD alone, suggesting that tissue loss was due mostly to parallel Alzheimer-type pathological changes and that the presence of Lewy bodies in cortical and subcortical neurons contributed little, if anything, to the overall degree of atrophy.

Aged↗
PubMed1995

Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques.

We analyzed an amino-terminal modification of beta-amyloid (A beta) peptide in brain, using anti-A beta antibodies that distinguish distinct molecular species. Examination of cortical sections from 28 aged individuals with a wide range in senile plaque density revealed that a molecular species distinct from the standard A beta is deposited in the brain in a dominant and differential manner. This modified A beta peptide (A beta N3(pE)) starts at the 3rd aminoterminal residue of the standard A beta, glutamate, converted to pyroglutamate through intramolecular dehydration. Because plaques composed of A beta N3(pE) are present in equivalent or greater densities than those composed of standard A beta bearing the first amino-terminal residue (A beta N1) and because deposition of the former species appears to precede deposition of the latter, as confirmed with specimens from Down's syndrome patients, the processes involved in A beta N3(pE) production and retention may play an early and critical role in senile plaque formation.

Adult↗
PubMed1995

A quantitative analysis of the incorporation of fibulin-1 into extracellular matrix indicates that fibronectin assembly is required.

Fibulin-1 is an extracellular matrix glycoprotein found in both loose and dense connective tissues, elastic fibers and some basement membranes. Cultured cells such as fibroblasts assemble endogenously synthesized or exogenously added fibulin-1 into matrix fibrils that also contain fibronectin. Since we have previously shown that fibulin-1 binds to fibronectin (Balbona, K., Tran, H., Godyna, S., Ingham, K. C., Strickland, D. K. and Argraves, W. S. J. Biol. Chem. 267: 20120-20125, 1992), we sought to investigate fibulin-1 incorporation into fibroblast extracellular matrix with an emphasis on evaluating the potential role of fibronectin in the process. In this study, we have used quantitative assays to measure the binding of 125I-fibulin to monolayers of cultured fibroblasts. Our results show that the kinetics of fibulin-1 incorporation into the cell layer and its partitioning into detergent-soluble and -insoluble fractions were similar to those of fibronectin. It was found that antibodies to fibronectin or to the fibulin-1-binding domain of fibronectin-inhibited fibulin-1 incorporation. Cell lines that fail to assemble fibronectin into the matrix, such as HT1080 or PFHR-9, do not incorporate fibulin-1 into their cell layers. However, when HT1080 cells were induced to assemble fibronectin by treatment with dexamethasone, they subsequently acquired the ability to incorporate fibulin-1. Moreover, treatment of cultured fibroblasts with antibodies that inhibit fibronectin assembly significantly inhibit fibulin-1 incorporation into the matrix. When increased amounts of fibronectin were incorporated into cells layers by incubating the cells for varying lengths of time with exogenous fibronectin, a corresponding increase in fibulin-1 incorporation was also observed. Taken together, the data indicate that the incorporation of fibulin-1 requires fibronectin assembly and suggests a dependence on the amount of fibronectin in a matrix. These results highlight the potential of fibronectin to control the deposition of fibulin-1 into those extracellular matrices where both proteins coincide and may have implications in the formation of fibulin-1-containing matrix structures such as basement membranes or elastic fibers.

Antibodies↗
PubMed1994

Delineation of the glycosaminoglycan-binding site in the human inflammatory response protein lactoferrin.

Lactoferrin is an iron-binding protein which is synthesized by mucosal epithelium and neutrophils and released by these cells in response to inflammatory stimuli. It promotes neutrophil aggregation and manifests iron-dependent and -independent antimicrobial properties in vitro. Since lactoferrin binds to glycosaminoglycans (GAGs) and sulfated polysaccharides can inhibit its clearance in vivo and in vitro, we sought to examine its interaction with the GAGs chondroitin sulfate and heparin. Amino-terminal sequencing of proteolytic fragments of human lactoferrin that were fractionated by GAG chromatography suggested that the amino-terminal 6 kDa of the secreted protein mediates its interaction with GAGs. Synthetic peptides were used to show that the first 33 residues of human lactoferrin can bind well to solid-phase or solution-phase GAGs. The first 33 residues bound fluoresceinamine-labeled heparin with an IC50 (611 nM) which approximated that of the intact protein (124 nM). In contrast, when the first six residues (GRRRRS) were removed from this peptide, it then bound poorly to heparin (IC50 = 49 microM). Our results suggest that the GRRRRS sequence at the amino terminus of human lactoferrin acts synergistically with an RKVR sequence at positions 28-31 to form the predominate functional GAG-binding site of human lactoferrin. Molecular modeling of the crystalline structure of lactoferrin supports a synergistic activity between these two sites since it shows that they juxtapose each other on the surface of the folded protein. Solid docking calculations indicate that they can form a cationic cradle as a binding site for chondroitin sulfate.

Amino Acid Sequence↗
PubMed1994

Postmortem brains reveal similar but not identical amyloid precursor protein-like immunoreactivity in Alzheimer compared with other dementias.

Concentrations of amyloid precursor protein (APP)-like immunoreactivity (APPLIR) have been determined by Western blotting in a soluble fraction and two membrane fractions of two areas of brain cortex from patients with Alzheimer's disease (AD) and other dementias. There were no significant differences between AD and other cases in species with the Kunitz protease inhibitor domain. However, the total soluble APPLIR was higher in AD and it was hypothesized that this relates to cholinergic hypoactivity.

Aged↗