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At least 739 records · Page 41Linked to original sources
PubMed1998

Isolation and functional characterization of cDNA of serum amyloid A-activating factor that binds to the serum amyloid A promoter.

Serum amyloid A (SAA), a plasma protein inducible in response to many inflammatory conditions, is associated with the pathogenesis of several diseases including reactive amyloidosis, rheumatoid arthritis, and atherosclerosis. We have previously reported an element of the SAA promoter, designated SAA-activating sequence (SAS), that is involved in the inflammation-induced SAA expression, and a nuclear factor, SAS-binding factor (SAF), that interacts with the SAS element has been identified previously (A. Ray and B. K. Ray, Mol. Cell. Biol. 16:1584-1594, 1996). To evaluate how SAF is involved in SAA promoter activation, we have investigated structural features and functional characteristics of this transcription factor. Our studies indicate that SAF belongs to a family of transcription factors characterized by the presence of multiple zinc finger motifs of the Cys2-His2 type at the carboxyl end. Of the three cloned SAF cDNAs (SAF-1, SAF-5, and SAF-8), SAF-1 isoform showed a high degree of homology to MAZ/ZF87/Pur-1 protein while SAF-5 and SAF-8 isoforms are unique and are related to SAF-1/MAZ/ZF87/Pur-1 at the zinc finger domains but different elsewhere. Although structurally distinct, all members are capable of activating SAS element-mediated expression and display virtually identical sequence specificities. However, varying levels of expression of members of this gene family were observed in different tissues. Functional activity of SAF is regulated by a posttranslational event as SAF DNA-binding and transactivation abilities are increased by a protein phosphatase inhibitor, okadaic acid, and inhibited by a protein kinase inhibitor, H7. Consistent with this observation, increased DNA binding of the cloned SAF and its hyperphosphorylation, in response to okadaic acid treatment of the transfected cells, were observed. Taken together, our results suggest that, in addition to tissue-specific expression, SAFs, a family of zinc finger transcription factors, undergo a modification by a posttranslational event that confers their SAA promoter-binding activity and transactivation potential.

Amino Acid Sequence↗
PubMed1994

Localization of Alzheimer amyloid beta protein precursor and its relation to senile plaque amyloid.

The authors examined the ultrastructural localization of amyloid beta protein precursor (APP) in normal human brains immunohistochemically using 3 kinds of APP antisera. The patterns of immunoreaction differed between the antisera used. Antiserum 770, against APP1-770, predominantly labeled the cytoplasm of neurons, whereas antiserum Z31, against the pre-beta region of the APP, labeled astroglial processes intensely and neurons to a lesser extent. Antiserum 1736, against the N terminal of beta protein, labeled both neurons and astrocytes. Vascular smooth muscle cells and some of the endothelial cells in the cerebral arterioles and capillaries were labeled with Z31 and 1736. The APP exists in every cells, while various patterns of immunoreactivity may reflect the difference in the metabolic pathway of APP between cell types.

Aged↗
PubMed2005

GM1 ganglioside and the seeding of amyloid in Alzheimer's disease: endogenous seed for Alzheimer amyloid.

A fundamental question about the pathogenesis of Alzheimer's disease (AD) is how monomeric, nontoxic amyloid beta-protein (Abeta) is converted to its toxic aggregates in the brain. The author previously identified a unique Abeta species in the AD brain, which is characterized by its binding to GM1 ganglioside (GM1). On the basis of the molecular characteristics of GM1-bound Abeta (GAbeta), the author hypothesized that GM1 plays a critical role in the process. The author recently examined this possibility using a novel monoclonal antibody raised against purified GAbeta and validated that GAbeta is endogenously generated in the brain and accelerates Abeta assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Abeta assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAbeta generation. The author's results imply a mechanism underlying the onset of AD and also provide a new insight into development of novel therapeutic strategy.

Aging↗
PubMed1996

Enzyme-linked immunosorbent assay for detection of feline serum amyloid A protein by use of immunological cross-reactivity of polyclonal anti-canine serum amyloid A protein antibody.

Immunological cross-reactivity between feline and canine serum amyloid A protein (SAA) was studied to establish enzyme-linked immunosorbent assay (ELISA) with heterologous antibody. Purified feline SAA formed a precipitin line in immunogel double diffusion with anti-canine SAA antibody. Immunological cross-reactivity was similarly observed in ELISA. In sandwich ELISA with anti-canine SAA antibody, a dose-response curve was obtained over the range of 2 micrograms/ml to 123 micrograms/ml of purified feline SAA. From the present findings, the sandwich ELISA is found to have high repeatability for quantitation of purified feline SAA and may be applicable to determine the serum concentration of feline SAA.

Animals↗
PubMed1999

Serum amyloid A1 alleles and plasma concentrations of serum amyloid A.

Serum amyloid A1 (SAA1), the predominant isotype of acute phase SAA in plasma and the predominant precursor of fibrillar deposits in reactive amyloidosis, is encoded by a gene, for which six allelic variants have been described. Recent studies proposed that the allele SAA1.3 was positively correlated with the development of reactive amyloidosis in Japanese. This study examined whether the plasma concentration of total SAA is influenced by specific SAA1 alleles. Two hundred and eighty healthy Japanese subjects were examined to determine the allelic distribution of SAA1 and SAA2 genes by the PCR-RFLP method, and to measure the total plasma SAA concentrations. SAA concentrations were significantly higher (p < 0.001) in subjects with the allele SAA1.5 than those without it, suggesting that SAA1.5 may have a distinctive feature in the process of synthesis or catabolism. Subjects with the allele SAA1.3 had lower SAA concentrations, though not statistically significant, than those with SAA1.1. There was not significant correlation of SAA2 alleles with SAA concentrations. These results are discussed in terms of amyloidogenicity.

Adult↗
PubMed2002

Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists.

Alzheimer's disease (AD) brain is characterized by excess deposition of amyloid beta-peptide (Abeta), particularly the 42-amino acid peptide [Abeta(1-42)] and by extensive oxidative stress. Several sources of the oxidative stress and inflammatory cascades are likely, including that induced by advanced glycation end products, microglial activation, and by Abeta(1-42) and its sequelae. This review briefly examines each of these sources of oxidative stress and inflammation in AD brain and discusses their potential roles in the clinical progression of AD dementia.

Acute-Phase Reaction↗
PubMed1999

Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene.

Protein kinase C (PKC)-activated modulation of amyloid precursor protein (APP) metabolism has been investigated in natural models of altered APP expression due to the presence of one, two or three copies of the APP gene. We show that levels of APP present in human skin fibroblasts strongly influence the effect of PKC activation of soluble APP (sAPP) release. Thus fibroblasts derived from a patient with a deletion in chromosome 21 including the APP locus (Delta21) had lower levels of both APP mRNA and cell-associated APP, and showed an exaggerated phorbol-ester-induced sAPP release, when compared with fibroblasts from control individuals. In contrast, fibroblasts from chromosome 21 trisomic Down's syndrome patients failed to show a concentration-dependent response to phorbol ester treatment. These results suggest that the levels of APP expression can affect the degree of response to PKC-mediated modulation of the metabolism of this protein.

Adult↗
PubMed2001

Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein.

Amyloid beta protein (Abeta) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Abeta, can be reversed with i.c.v. injections of an Abeta antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with (32)P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 +/- 0.39 microl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.

Alzheimer Disease↗
PubMed1992

Serum amyloid A changes high density lipoprotein's cellular affinity. A clue to serum amyloid A's principal function.

The affinity of high density lipoproteins (HDL), or HDL carrying serum amyloid A (HDL/SAA), for hepatocytes or peritoneal macrophages was examined, as part of an investigation exploring the principal function of SAA and how this may be related to amyloidogenesis. The binding results in conjunction with SAA's existence primarily on HDL during inflammation, and HDL's known "reverse cholesterol transport" function suggest a clear role for SAA in the afferent arm of the reverse cholesterol transport pathway during the process of inflammation. The presence of SAA reduced HDL's affinity for normal hepatocytes by a factor of 2. In contrast, HDL/SAA had a 3- to 4-fold higher affinity for macrophages than HDL alone. Furthermore, the number of binding sites for HDL/SAA increased on macrophages during inflammation, while decreasing on hepatocytes. The net effect was a significant shift in HDL cholesterol carrying capacity towards the macrophage. Competition experiments demonstrated that HDL/SAA is only half as effective as HDL in inhibiting radiolabeled HDL binding to macrophages. This is in keeping with the reduced apolipoprotein A-1 content in HDL/SAA. Strikingly, although HDL contains twice as much apolipoprotein A-1 as HDL/SAA, it is only one-tenth as effective as HDL/SAA in inhibiting radiolabeled HDL/SAA binding to macrophages. The latter results suggest that there is a specific SAA binding site on macrophages.

Animals↗
PubMed1993

Homozygous familial amyloidosis, Finnish type: demonstration of glomerular gelsolin-derived amyloid and non-amyloid tubular gelsolin.

The immunohistochemical findings in the kidneys of two sisters with homozygous familial amyloidosis of Finnish type, an autosomal dominant disorder of gelsolin catabolism, is described. The disease, manifesting with nephrotic syndrome and end-stage renal failure was characterized by heavy glomerular deposits of gelsolin-derived amyloid. Immunostaining also revealed the presence of gelsolin in the tubular epithelium that was Congo-red negative. It is concluded that homozygous Finnish amyloidosis leads to a severe nephropathy due to the deposition of fragments of mutant gelsolin.

Adult↗
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↗
PubMed1998

Examination of serum amyloid A protein in kidney transplant patients--comparison of serum amyloid A and C-reactive protein for monitoring the occurrence of renal-allograft-related complications.

Serum amyloid A (SAA) is an inflammation-reactive protein, like C-reactive protein (CRP). In this study, we examined SAA levels in the sera of kidney transplant patients with acute rejection (N = 12), chronic rejection (N = 60) and cytomegalovirus (CMV) infection complications and compared them with serum CRP levels in terms of sensitivity and reactivity. The SAA and CRP showed almost similar kinetics in 10 patients within 2 months of kidney transplantation. However, in 2 patients SAA responded more sensitively to CMV infection and acute rejection. SAA increased significantly 10-fold relative to its baseline levels. The SAA levels also increased along with those of serum creatinine levels. Our experiments clearly showed that SAA and CRP responded sensitively to several stimuli with elevated serum levels including surgical trauma, acute allograft rejection and infection. However, the reactivity and sensitivity of SAA was clearly higher than those of CRP in patients with viral infections, on steroid therapy and undergoing chronic allograft rejection, suggesting that monitoring SAA levels provides more useful information than monitoring CRP.

Biomarkers↗
PubMedDate not supplied

Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes.

Ten histologic sections were sampled from similar cortical regions in each of 84 autopsy brains removed from patients aged 60 to 97 years. The sections were stained by the Congo-red method and examined under polarized light for the presence of cortical (parenchymal) cerebral amyloid angiopathy (CAA). Some degree of CAA was found in 36% of all brains examined, with a higher proportion of patients affected in each successive decade of life. Angiopathy was seen most frequently and was of greater severity in the parietal and occipital gray matter. Overall, it was often a patchy and asymmetric lesion. There was sparing of subcortical white matter and the hippocampi. CAA was most severe in cases of Alzheimer's disease, but occurred in the absence of this condition.

Aged↗
PubMed1982

The role of interleukin 1 in acute phase serum amyloid A (SAA) and serum amyloid P (SAP) biosynthesis.

The acute phase SAA and SAP profiles have been compared for localized and endotoxin induced inflammation in LPS responder and nonresponder strains of mice. The SAP profile can reflect a delay with respect to the start of the increase. Its maximum is on the order of ten times the nonacute phase concentration and elevated concentrations are sustained 24 to 48 hours after SAA concentration is rapidly decreasing to normal. The role of Interleukin 1, known to have an essential role in SAA production, was investigated for SAP production. Purified mouse IL 1 and rabbit IL 1 produced a minimal elevation of SAP concentration above normal values, especially when compared with their effects on SAA concentration. BCG infection was shown to synergistically augment SAA induction by LPS and was shown to enhance IL 1 production by macrophages in response to LPS. Unlike SAA synthesis, BCG-preinfection fails to synergistically augment the LPS-induced SAP response. BCG infection alone produced highly elevated and sustained increases in SAP concentration, whereas, the effect on SAA concentration was minimal. Macrophages appear to play an important role in SAP acute phase elevation, but the mechanism in different from that of SAA elevation.

Acute Disease↗