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PubMed1999

A deletion polymorphism of alpha(2)-macroglobulin gene and cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: alpha(2)-Macroglobulin may be implicated in amyloid beta protein deposition. A deletion in the exon 18 splice acceptor of the alpha(2)-macroglobulin gene (A2M) has been reported to be associated with risk for Alzheimer's disease (AD). In search of genetic risk factors for cerebral amyloid angiopathy (CAA), we investigated association of the A2M deletion polymorphism with CAA. METHODS: The association between the severity of CAA and A2M deletion polymorphism was investigated in 178 autopsy cases of the elderly including 68 patients with AD. RESULTS: There was no significant difference in the severity of CAA between individuals with the A2M deletion allele and those without in the AD, non-AD, or total cases. Status for the epsilon4 allele of the apolipoprotein E gene did not influence the results. CONCLUSIONS: Our results suggest that the A2M deletion polymorphism may not be a definitive risk factor of CAA in the elderly, although further study with larger samples is necessary to confirm this.

Aged↗

PubMed1989

Alpha-macroglobulin secreted by alveolar macrophages serves as a binding protein for a macrophage-derived homologue of platelet-derived growth factor.

Evidence is presented to support our hypothesis that an alpha-macroglobulin (alpha M) produced by lung macrophages serves as a specific binding protein for platelet-derived growth factor (PDGF) from these same macrophages. Culture medium "conditioned" by alveolar macrophages was fractionated by gel filtration according to molecular weight. Proteins larger than 200 kD were bound to greater than 50% of the macrophage-derived PDGF (MD-PDGF) that was extractable by 1 M acetic acid. Another approximately 25% was bound to fractions at approximately 150 kD, and approximately 20% remained unbound. The two high molecular weight fractions inhibited approximately 40% of specific [125I]PDGF binding to rat lung fibroblasts, whereas other fractions did not block PDGF binding to its receptor. Only the greater than 200 kD fractions inhibited the binding of PDGF antisera to purified human PDGF by 20% of control and exhibited specific complex formation and coelution on a gel filtration column with [125I]PDGF. The macrophage-derived alpha M (MD-alpha M) was separated from other macrophage-derived proteins by nickel-affinity chromatography and exhibited clear characteristics of alpha Ms, i.e., cross-reactivity with antibodies to human alpha 2-macroglobulin (alpha 2M) on immunoblots as well as gel migration corresponding to the electrophoretic mobility of the protease-bound "fast" and protease-unbound "slow" forms of human alpha 2M. Nickel-bound protein identified as an alpha M was bound to greater than 50% of the acid-extractable MD-PDGF in macrophage-conditioned medium, supporting the view that the greater than 200 kD protein separated by gel filtration is an alpha M.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1969

Development of gamma G, gamma A, gamma M, beta IC-beta IA, C 1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, plasminogen, alpha 1-antitrypsin, orosomucoid, beta-lipoprotein, alpha 2-macroglobulin, and prealbumin in the human conceptus.

The synthesis of gammaG, gammaA, gammaM, beta(1C)/beta(1A), C'1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, alpha(1)-antitrypsin, orosomucoid, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin was studied in 15 normal human embryos and fetuses of 29 days to 18 wk gestation and in the yolk sacs of four embryos from 5.5 to 11.5 wk gestation using tissue culture in (14)C-labeled amino acids followed by radioimmunoelectrophoresis. The human embryo as early as 29 day gestation synthesized beta(1C)/beta(1A), C'1 esterase inhibitor, transferrin, hemopexin, alpha(1)-antitrypsin, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin in culture. At 32 days gestation ceruloplasmin and orosomucoid were also synthesized, but synthesis of fibrinogen was not observed before 5.5 wk. Synthesis of gammaM occurred as early as 10.5 wk gestation, and gammaG synthesis was found in cultures as early as 12 wk gestation; gammaA synthesis was not detected in any of the tissue cultures. With the exception of the gamma-globulins, each of the proteins studied was synthesized by the liver, but additional sites of synthesis for some of these proteins were also found. Synthesis of gammaG and gammaM occurred primarily in the spleen, but other sites of synthesis were noted as well. Changes in the concentrations of most of these proteins and plasminogen in embryonic and fetal serum from 5.5 to 41 wk gestation, in amniotic fluid from 6.5 to 38 wk gestation, and in the sera of neonates during the 1st 3 wk postpartum are described. Although gammaA, gammaM, ceruloplasmin, or haptoglobin were not detectable in some of the embryonic and fetal sera, gammaA and ceruloplasmin were both present as early as 6.5 wk gestation, haptoglobin by 9.5 wk gestation, and gammaM by 17 wk gestation. Each of the other proteins were present in all of the sera examined.

Abortion, Therapeutic↗

PubMed2000

Alpha2 macroglobulin and the risk of Alzheimer's disease.

BACKGROUND: alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56). METHODS: We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism. RESULTS: We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors. CONCLUSIONS: Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

Aged↗

PubMed2005

Evaluation of the cardiac isoform of alpha2-macroglobulin as a factor inducing cardiac hypertrophy.

Earlier studies from our laboratory showed that a 182-kDa high-molecular-weight protein appeared during early stages of development of cardiac hypertrophy in animals subjected to aortic constriction. Later it was confirmed that this protein is a cardiac isoform of alpha2-macroglobulin belonging to the macroglobulin family. Furthermore, it has been demonstrated that direct injection of the purified 182-kDa protein intravenously (through the tail vein) into the normal animals led to the development of cardiac hypertrophy. It was accompanied by enlargement of cardiac myocytes and induction of beta-myosin heavy chain (MHC) and MLC-2 gene expression. Multiple injections of 182-kDa protein-specific polyclonal antibody into the circulation of aorta-constricted animals completely abolished the development of hypertrophy and downregulated the expression of beta-MHC and myosin light chain (MLC)-2. The full-length cDNA of the 182-kDa protein cloned in eukaryotic expression vector, namely, pcDNA 3.1(-) could induce cardiac hypertrophy upon direct injection into rat heart. Hypertrophy was monitored by determining the heart weight/body weight ratio and also by Northern blot analysis of muscle-specific marker genes such as beta-MHC, MLC-2, and antrial natriuretic factor. Also, induction of promoter activity of beta-MHC and c-fos genes analyzed by chloramphenicol acetyl transferase assay confirmed the induction of cardiac hypertrophy upon direct injection of the full-length cDNA of the 182-kDa protein.

Animals↗

PubMed2005

A new selective substrate for cathepsin E based on the cleavage site sequence of alpha2-macroglobulin.

Cathepsin E is an intracellular aspartic proteinase of the pepsin family predominantly expressed in cells of the immune system and believed to contribute to homeostasis by participating in host defense mechanisms. Studies on its enzymatic properties, however, have been limited by a lack of sensitive and selective substrates. For a better understanding of the importance of this enzyme in vivo, we designed and synthesized a highly sensitive peptide substrate for cathepsin E based on the sequence of the specific cleavage site of alpha2-macroglobulin. The substrate constructed, MOCAc-Gly-Ser-Pro-Ala-Phe-Leu-Ala-Lys(Dnp)-D-Arg-NH2 [where MOCAc is (7-methoxycoumarin-4-yl)acetyl and Dnp is dinitrophenyl], derived from the cleavage site sequence of human alpha2-macroglobulin, was the most sensitive and selective for cathepsin E, with k(cat)/K(m) values of 8-11 microM(-1) s(-1), whereas it was resistant to hydrolysis by the analogous aspartic proteinases cathepsin D and pepsin, as well as the lysosomal cysteine proteinases cathepsins B, L, and H. The assay allows the detection of a few fmol of cathepsin E, even in the presence of plasma and cell lysate, and gives accurate results over a wide enzyme concentration range. This substrate might represent a useful tool for monitoring and accurately quantifying cathepsin E, even in crude enzyme preparations.

Animals↗

PubMed1982

Subunit structure of the rat alpha-macroglobulin proteinase inhibitors.

Rats produce 2 alpha-macroglobulin (alpha M) proteinase inhibitors, the alpha 1 M, normally found in the plasma, and the alpha 2 M, an acute phase protein. The alpha-macroglobulins were purified from the plasma of rats with adjuvant arthritis by polyethylene glycol precipitation, chromatography on a Zn2+ affinity column, and filtration on Sephacryl S-300 superfine. Comparison of the purified proteins on sodium dodecyl sulfate polyacrylamide gel electrophoresis following reduction reveals a 185 000 Da subunit for rat alpha 2 M identical to the human alpha 2 M, but a 167 000 plus a 38 000 Da subunit for rat alpha 1 M. Heat/alkali treatment (pH 11, 37 degrees C for 45 min) prior to reduction results in the appearance of 125 000 Da and 60 000 Da components from rat alpha 2 M analogous to the pattern of human alpha 2 M. In contrast, alpha 1 M showed in addition to the 125 000 Da band (and the unaltered 38 000 Da band), two bands of approx. 25 000 Da. Incubation with trypsin (approximately 1 mol/mol alpha M) prior to reduction causes formation of approximately 90 000 Da components from both rat inhibitors and the human alpha 2 M. The data suggests that only rat alpha 2 M and not rat alpha 1 M is structurally homologous to human alpha 2 M.

Animals↗

PubMed1982

Computer averaging of single molecules of alpha 2-macroglobulin and the alpha 2-macroglobulin/trypsin complex.

From electron micrographs single molecules of alpha 2-macroglobulin in the "closed" form, the "open" form and as the trypsin complex have been computer averaged. The molecular images are discussed. Molecules of the electrophoretically fast migrating "F-form" have the "closed" form. In the case of the alpha 2-macroglobulin/trypsin complex the two attached trypsin molecules are located very near to each other and in the central part of the alpha 2-macroglobulin molecule.

Computers↗

PubMed1994

Interactions of alpha-1-antichymotrypsin, alpha-1-proteinase inhibitor, and alpha-2-macroglobulin with the fungal enzyme, seaprose.

The Semi-alkaline proteinase (Seaprose) from Aspergillus melleus has been tested for its ability to either inactivate or form complexes with three human plasma proteinase inhibitors, alpha-2-macroglobulin, alpha-1-antichymotrypsin and alpha-1-proteinase inhibitor. alpha-2-Macroglobulin was found to inhibit Seaprose, with two mol of enzyme being complexed per mol of inhibitor. However, alpha-1-proteinase inhibitor was rapidly inactivated by the fungal enzyme as a result of cleavage of the inhibitor, primarily at the P1-P'1 reactive site. Curiously, alpha-1-antichymotrypsin was found to form complexes with Seaprose and also be inactivated by this inhibitor. Apparently, the enzyme can recognize two sites within the reactive site loop of the inhibitor, one at the P4-P'5 position, resulting in inactivation, and one presumably at the P1-P'1 reactive site which results in complex formation. The fact that Seaprose can so rapidly inactivate alpha-1-proteinase inhibitor, the primary regulator of neutrophil elastase, indicates that Seaprose would be a rather poor choice for therapy in individuals with bronchial mucus hypersecretion.

Amino Acid Sequence↗

PubMed1980

The determination of antithrombin III, alpha 2-macroglobulin and alpha 2-antiplasmin in plasma by laser nephelometry.

Specific assay procedures were developed to determine antithrombin III, alpha 2-macroglobulin, and alpha 2-antiplasmin in plasma with the aid of a Laser nephelometer. About 100 normal and pathological plasmas were examined and the results compared with those obtained by conventional immunological methods, such as radial immunodiffusion or rocket electrophoresis. Nephelometry proved to be a very rapid, precise, and reproducible method for the determination of antithrombin III and alpha 2-macroglobulin. The reproducibility of the alpha 2-antiplasmin assay was poor, probably as a consequence of the low concentration of this inhibitor in normal plasma.

Antithrombin III↗

PubMed1987

Functional levels of alpha 2-macroglobulin in plasma in relation to emphysema.

In most studies, concentrations of alpha 2-macroglobulin are determined by immunological techniques. In this study, the amidolytic activity of porcine pancreatic elastase complexed with alpha 2-macroglobulin was measured using an elastase-specific substrate, succinyl-trialanyl-p-nitroanilide. The activities of plasmas from 47 emphysema cases were compared with 39 normal subjects. The age ranges of both groups were from 50 to 84 years. The mean activity of bound elastase in emphysema cases was 2.48 +/- 0.03 kU/l of plasma. The mean for normal subjects was 1.48 +/- 0.11 kU/l of plasma. The difference was very significant (2P less than 0.001). All except 2 of the emphysema cases had smoked. The same results were obtained when only people who had smoked for 25 years or more were included in the analysis. All the plasma samples of people included in the study were assayed by an immunological method for absolute level (in g/l) of alpha 1-proteinase inhibitor. The levels of alpha 1-proteinase inhibitor for all the persons studied fell within the normal range for MM-phenotypes (2 to 4 g/l).

Aged↗

PubMed1987

Determination of functional activity of alpha 1-protease inhibitor and alpha 2-macroglobulin in human plasma using elastase.

The competitive binding of human alpha 1-antitrypsin and human alpha 2-macroglobulin to porcine pancreatic elastase was studied. Mixtures of these two protease inhibitors, when titrated against elastase give inhibition curves analogous to those obtained with human plasma. This is however not the case when the individual inhibitors are used. A theoretical treatment enabled us to devise an assay method to determine the amounts of functional activity of alpha 1-protease inhibitor and alpha 2-macroglobulin respectively in human plasma.

Animals↗

PubMedDate not supplied

An inhibition ELISA to determine alpha macroglobulin levels in mouse plasma.

A sensitive method for quantifying mouse plasma alpha-macroglobulins (AM) using an inhibition ELISA is described. AM are important plasma proteinase inhibitors that possibly act also as immunomodulatory molecules. The standard protocol developed in our experiments involves coating well with 10 micrograms/ml A2M in carbonate buffer, followed by incubation with a 1:1 (v/v) mixture of the plasma to be tested (diluted 1/1000) and goat anti-AM (diluted 1/1250). This is followed by further incubation, first with the enzyme-conjugated antibody and with the substrate prior to the reading of absorbance levels of the reaction products. Standard curve samples must be included in each plate, employing known amounts of the purified Murine Alpha-2-Macroglobulin (MuA2M) used for coating, with concentrations ranging from 0.001 to 10 micrograms/ml. Using test samples in triplicates and a 6-point standard curve in a single ELISA plate, 25 plasma samples can be tested accurately. The method offers an useful tool for establishing AM levels in small samples of mouse plasma.

Animals↗

PubMed1979

Preparation of anti-alpha 2-macroglobulin using Canavalia lineata DC lectin for differentiating species-specificity of blood stains.

To differentiate species-specificity of blood stains, anti-alpha 2-macroglobulin was raised in rabbits against Canavalia lineata DC lectin-serum complex (LSC). Adsorption of anti-LSC with human lipoprotein resulted in antiserum specific for alpha 2-macroglobulin. It was confirmed by Ouchterlony test that the antiserum adsorbed successively with monkey serum or anti-LSC adsorbed directly with monkey serum reacted with only human serum but not with mammalian ones. Immunoelectrosyneresis and anti-LSC consumption test could identify species-specificity of blood stains kept for up to two years and for up to several years, respectively. It is indicated that anti-LSC is quite effective for differentiating species-specificity of blood stains.

Adsorption↗

PubMed1983

Comparative studies on the serum levels of alpha-1-antitrypsin and alpha-macroglobulin in several mammals.

The sera of human, cattle, horse, sheep, goat, pig, dog, rabbit, guinea pig, rat, hamster, and mouse were assayed for total trypsin-inhibiting capacity, and for concentrations of alpha-1-antitrypsin and alpha-macroglobulin. The rodents examined showed striking species differences: the alpha-1-antitrypsin levels of mouse, rat, and guinea pig were more than twice the human level, while the alpha-macroglobulin levels of hamster and guinea pig were 340 and 40%, respectively, of the human level. On the other hand, little variations were found among the large domestic animals, their levels of the two inhibitors being similar to those of the human.

Animals↗

PubMed2002

Selective precipitation of haptoglobin and alpha2-macroglobulin from human serum using Alocasia macrorhiza tuber protein.

Treatment of human serum with ammonium sulfate fraction (0-50%) of Alocasia macrorhiza tuber extract resulted in precipitation at neutral pH. The precipitate was dissolved at pH 10.5 and chromatographed on Sephadex G-100 column. Two protein peaks were resolved. While the first peak represented alpha2-macroglobulin and haptoglobin, the second peak accounted for specific Alocasia protein. Incidentally the Alocasia protein was shown to be responsible for selective and specific precipitation of alpha2-macroglobulin and haptoglobin from serum. Thus the plant protein in its pure form or in crude stage could be used for the rapid isolation of two of the prominent alpha2-globulins.

Alocasia↗

PubMed1982

alpha 2-Antiplasmin and alpha 2-macroglobulin--the main inhibitors of fibrinolysis--during the menstrual cycle, pregnancy, delivery, and treatment with oral contraceptives.

alpha 2-Antiplasmin and alpha 2-macroglobulin have been studied during the menstrual cycle, pregnancy and parturition in healthy women, and during use of various types of contraception in both healthy and diabetic women, and compared with a reference group of healthy men and women. alpha 2-Antiplasmin showed a slight sex difference, with higher values in women. The luteal phase of the menstrual cycle showed slightly higher values than the other phases. alpha 2-Antiplasmin increased during pregnancy, decreased (probably due to consumption) during labor and increased again in the puerperium. Treatment with neither combined contraceptive pills nor low dose progestogen pills gave any changes in alpha 2-antiplasmin. alpha 2-Macroglobulin showed low values during menstruation. The increase during pregnancy and treatment with combined contraceptive pills is in accordance with earlier findings. It is concluded that synthesis and metabolism of alpha 2-antiplasmin are under hormonal influence. The role of alpha 2-antiplasmin in the decreased fibrinolysis in pregnancy is discussed.

Adolescent↗

PubMed1990

Molecular distribution of elastase between its two main inhibitors: direct quantitation of elastase-alpha 2-macroglobulin complex with a novel ELISA technique.

A novel enzyme-linked immunosorbent assay for the quantitation of elastase linked to alpha 2-macroglobulin (alpha 2M) (elastase-alpha 2M complex, EMC) in body fluids is presented. The assay has a lower detection limit of 1.5 ng bound elastase per ml. The critical factor allowing immunological detection of alpha 2M-bound elastase is the addition of phenyl methyl sulphonyl fluoride (PMSF) to the assay buffer. The assay has been used to quantitate EMC in plasma and serum of healthy volunteers, and assess the distribution of elastase between its two main inhibitors, alpha 2M and alpha 1-proteinase inhibitor (API). EMC levels in serum samples from volunteers were significantly higher than in plasma (26.9 vs 21.9 ng/ml, p = 0.05, Student's t-test for paired samples). The API-bound elastase levels were 70.2 and 170.1 ng/ml in plasma and serum respectively (statistically significantly higher in serum, p less than 0.0001). The ratio of macroglobulin to alpha 1-proteinase-bound elastase levels was 0.333 in plasma and 0.168 in serum (p less than 0.0001). As alpha 2M bound elastase retains some proteolytic activity, direct measurement of circulating levels in inflammatory conditions should be of interest.

Chromatography, Gel↗