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PubMed1992

The complete amino acid sequence of bovine serum amyloid protein A (SAA) and of subspecies of the tissue-deposited amyloid fibril protein A.

Bovine serum amyloid A (SAA) was isolated from the acute phase high density lipoprotein (HDL) fraction of a cow suffering from acute mastitis. The elucidated primary structure revealed a protein consisting of 112 amino acid residues. Compared with SAA proteins from other species, the bovine protein was shown to have an insertion of nine amino acid residues between positions 69 and 70. No microheterogeneity could be observed in the protein. Amyloid fibrils extracted from the kidneys were found to contain at least three subspecies of protein AA, consisting of 68, 81 and about 110 amino acid residues. The amino acid sequences established for the protein AA subspecies revealed no microheterogeneity, and were identical to that elucidated for protein SAA.

Amino Acid Sequence↗
PubMed2005

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates.

Recently, a novel plaque-associated protein, collagenous Alzheimer amyloid plaque component (CLAC), was identified in brains from patients with Alzheimer's disease. CLAC is derived from a type II transmembrane collagen precursor protein, termed CLAC-P (collagen XXV). The biological function and the contribution of CLAC to the pathogenesis of Alzheimer's disease and plaque formation are unknown. In vitro studies indicate that CLAC binds to fibrillar, but not to monomeric, amyloid beta-peptide (Abeta). Here, we examined the effects of CLAC on Abeta fibrils using assays based on turbidity, thioflavin T binding, sedimentation analysis, and electron microscopy. The incubation of CLAC with preformed Abeta fibrils led to increased turbidity, indicating that larger aggregates were formed. In support of this contention, more Abeta was sedimented in the presence of CLAC, as determined by gel electrophoresis. Moreover, electron microscopy revealed an increased amount of Abeta fibril bundles in samples incubated with CLAC. Importantly, the frequently used thioflavin T-binding assay failed to reveal these effects of CLAC. Digestion with proteinase K or trypsin showed that Abeta fibrils, incubated together with CLAC, were more resistant to proteolytic degradation. Therefore, CLAC assembles Abeta fibrils into fibril bundles that have an increased resistance to proteases. We suggest that CLAC may act in a similar way in vivo.

Alzheimer Disease↗
PubMed2002

Nicotine reduces the secretion of Alzheimer's beta-amyloid precursor protein containing beta-amyloid peptide in the rat without altering synaptic proteins.

Alzheimer's disease (AD) is characterized by cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). Altered metabolism of beta APP, resulting in increased A beta production, appears central in the neuropathology of AD. The processing of the holoprotein beta APP by different "secretase" enzymes results in three major carboxyl-truncated species. One species, which results from the cleavage of beta APP by gamma-secretase, is secreted into the cerebrospinal fluid (CSF) and is called sAPP gamma as it contains an intact A beta domain. Moreover, AD is characterized by cholinergic dysfunction and the loss of synaptic proteins. Reports of an inverse relation between nicotine intake, due to cigarette smoking, and the incidence of AD prompted us to investigate the effects of nicotine on beta APP processing and synaptic proteins in rats and in cell culture. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking, and a higher but well tolerated dose, respectively, was administered over 14 days to rats. Levels of sAPP in the CSF sample were evaluated by Western blot analysis. The higher dose significantly increased levels of total sAPP; however, both doses significantly reduced sAPP gamma, which contains the amyloidogenic portion of A beta. These actions were blocked by nicotinic receptor antagonism. Nicotinic antagonists alone had no effect on either total sAPP or sAPP gamma levels in CSF. Nicotine did not significantly change the intracellular levels of total beta APP in rat brain extracts, which is consistent with neuronal cell culture data. Similarly, levels of vesicular protein, such as synaptophysin, and presynaptic terminal protein SNAP-25 were unaffected by nicotine treatment both in vivo and in cell culture experiments. Taken together, these results suggest that nicotine modifies beta APP processing away from the formation of potentially amyloidogenic products, without altering the levels of synaptic proteins, and that this can potentially offer therapeutic potential for Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed2002

Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms.

Both tau and beta-amyloid 42 (Abeta42) have been implicated in Alzheimer's disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Abeta42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson's disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Abeta42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Abeta42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of beta-amyloid or axonal degeneration.

Aged↗
PubMed2002

Antibodies to beta-amyloid decrease the blood-to-brain transfer of beta-amyloid peptide.

Amyloid-beta peptides (Abeta) play an important role in the pathophysiology of dementia of the Alzheimer's type and in amyloid angiopathy. Abeta outside the CNS could contribute to plaque formation in the brain where its entry would involve interactions with the blood-brain barrier (BBB). Effective antibodies to Abeta have been developed in an effort to vaccinate against Alzheimer's disease. These antibodies could interact with Abeta in the peripheral blood, block the passage of Abeta across the BBB, or prevent Abeta deposition within the CNS. To determine whether the blocking antibodies act at the BBB level, we examined the influx of radiolabeled Abeta (125I-Abeta(1-40)) into the brain after ex-vivo incubation with the antibodies. Antibody mAb3D6 (élan Company) reduced the blood-to-brain influx of Abeta after iv bolus injection. It also significantly decreased the accumulation of Abeta in brain parenchyma. To confirm the in-vivo study and examine the specificity of mAb3D6, in-situ brain perfusion in serum-free buffer was performed after incubation of 125I-Abeta(1-40) with another antibody mAbmc1 (DAKO Company). The presence of mAbmc1 also caused significant reduction of the influx of Abeta into the brain after perfusion. Therefore, effective antibodies to Abeta can reduce the influx of Abeta(1-40) into the brain.

Amino Acid Sequence↗
PubMed2005

Purification of amyloid protein AA subspecies from amyloid-rich human tissues.

Protein AA, the major amyloid fibril protein in reactive (secondary) systemic amyloidosis is derived from the acute phase reactant liver-produced apolipoprotein serum AA (SAA) by proteolytic cleavage, usually in the C-terminal half of the 104 amino acid residues long precursor. The cleavage points in SAA vary between patients and the deposited protein AA is often quite heterogeneous. In this chapter, we describe methods to extract amyloid fibrils and to purify protein AA by sequential gel filtration. Further purification of subspecies of protein AA is best achieved by the use of differences in charge and chromatofocusing is described as the method of choice. Analytic methods include sodium dodecylsulfate polyacrylamide gel electrophoresis and analytic isoelectric focusing.

Humans↗
PubMed2002

Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense.

Serum amyloid A (SAA) is a family of closely related apolipoproteins associated with high density lipoprotein (HDL). Subclasses of SAA isoforms are differentially expressed constitutively and during inflammation. During states of infection or inflammation, levels of HDL bound, acute phase isoforms of SAA rise as much as 1000-fold in the serum, suggesting that it might play a role in host defense. Following recurrent or chronic inflammation, an N-terminal peptide fragment of SAA known as amyloid A (AA) assembles into fibrils causing extensive damage to spleen, liver, and kidney, and rapidly progressing to death. In the present paper, we report the novel finding that a recombinant acute phase isoform variant of human SAA 1.1 (SAAp) readily forms ion-channels in planar lipid bilayer membranes at physiologic concentrations. These channels are voltage-independent, poorly selective, and are relatively long-lived This type of channel would place a severe metabolic strain on various kinds of cells. Expression of human SAA 1.1 in bacteria induces lysis of bacterial cells, while expression of the constitutive isoform (human SAA4) does not. Secondary structural analysis of the SAA isoforms in dicates a strong hydrophobicity of the N-terminal of the acute phase isoform relative to the constitutive SAA4 isoform, which may be responsible for the bactericidal activity of the former, in keeping with the notion that SAA 1 targets cell membranes and forms channels in them. Channel formation may thus be related to a host defense role of acute phase SAA isoforms and may also be the mechanism of end organ damage in AA and other amyloidoses.

Amino Acid Sequence↗
PubMed2002

Peptides corresponding to gelsolin derived amyloid of the finnish type (AGelFIN) adopt two distinct forms in solution of which only one can polymerize into amyloid fibrils and form complexes with apoE.

Familial amyloidosis of the Finnish type is caused by a point mutation at position 187 of gelsolin. The mutation generates a proteolytic fragment, which forms amyloid fibrils in vivo. In the present study we have elucidated the aggregation properties of synthetic peptides corresponding to the wild type and mutated gelsolin fragments. We show by high performance size exclusion chromatography and mass spectrometry that a part of these peptides polymerize with an increase in incubation time, while a portion of the same peptide can adopt a soluble, non-polymerizing structure. Peptides that remain soluble are in their monomeric stage, while the polymerizing peptides prefer a dimerized intermediate stage. We also show that the initialform of these peptides in the solution dramatically influence their capability to interact with amlyloid associated proteins, such as apolipoprotein E. Our results indicate that the amyloidogenic fragment of gelsolin can adopt two distinct forms, of which only one can form amyloid fibrils in vitro.

Amyloid↗
PubMed2005

Non A beta component of Alzheimer's disease amyloid and amyloid beta peptides evoked poly(ADP-ribose) polymerase-dependent release of apoptosis-inducing factor from rat brain mitochondria.

Amyloid beta peptide (A beta) and non-A beta component of Alzheimer's disease amyloid (NAC) are involved in pathomechanism of Alzheimer's Disease (AD) and are deposited in the AD brain in the form of senile plaques. However, the mechanism of their neurotoxicity is not fully understood. In this study the sequence of events involved in NAC and A beta peptides evoked toxicity was investigated in brain slices, synaptosomes and in subcellular fractions. Radio-, immunochemical, spectrophotometrical methods and DNA electrophoresis were used in this study. Our data indicated that A beta 1-40 (25 microM) and NAC (10 microM) peptides induced liberation of free radicals and massive DNA damage that lead to activation of DNA bound enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In consequence of these processes apoptosis-inducing factor (AIF) was released from mitochondria and was translocated to nucleus. The inhibitor of PARP, 3-aminobenzamide significantly decreased AIF release from mitochondria and its translocation. Both peptides under the investigational conditions had no effect on caspase-3 activity. Our data indicated that A beta and NAC peptides stimulate AIF-dependent apoptotic pathway that seems to be caspase independent process. The inhibition of PARP-1 may protect the brain against A beta and NAC toxicity.

Amyloid beta-Peptides↗
PubMed2005

Plasma beta carotene in Alzheimer's disease. Association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), beta-amyloid 1-42 (Abeta42) and total Tau.

We studied the plasma beta carotene concentrations in 40 Alzheimer's disease patients and the association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), cerebrospinal fluid beta-amyloid 1-42 (Abeta42) and cerebrospinal fluid total Tau. We found that patients with plasma beta carotene levels below the 25th percentile had 55% reduced ratios of Abeta40/Tau and 51% reduced ratios of Abeta 40/Abeta 42 compared with patients in the highest quartile. Mean Tau concentrations in the lowest quartile of plasma beta-carotene levels were 74% higher compared with the highest quartile of plasma beta-carotene levels. Thus, we could demonstrate an statistically significant association between beta carotene levels in plasma and neurochemical markers in the cerebrospinal fluid of Alzheimer's disease patients.

Aged↗
PubMed1986

Is the serum amyloid A protein in acute phase plasma high density lipoprotein the precursor of AA amyloid fibrils?

Serum amyloid A protein (SAA), an apolipoprotein of high density lipoprotein (HDL), is generally considered to be the precursor of AA protein, which forms the fibrils in reactive systemic amyloidosis in man and animals. This view is based on amino acid sequence identity between AA and the amino-terminal portion of SAA. However, in extensive and well-controlled studies of experimentally induced murine AA amyloidosis, we were unable to demonstrate a direct precursor-product relationship between SAA, in SAA-rich HDL preparations from acute phase or amyloidotic mouse or human serum, and AA protein in the amyloid deposits. This raises the possibility that SAA in its usual form, as an apolipoprotein of HDL synthesized during the acute phase response, may not be the major precursor of AA fibrils. The amyloidogenic forms of circulating SAA molecules may not be isolated during the preparation of HDL. Alternatively, particularly in the light of recent evidence that SAA mRNA is expressed in many different tissues throughout the body of appropriately stimulated animals, amyloidogenic SAA may be derived from sources other than the liver cells in which SAA-rich HDL is synthesized.

Acute-Phase Reaction↗
PubMed1987

Production of an amino acid sequence-specific antiserum against human amyloid A (AA) and serum amyloid A (SAA) protein.

The hydrophilic nonapeptide Ser-Asp-Ala-Arg-Glu-Asn-Ile-Gln-Arg, identical with residues 59-67 of human amyloid protein A (AA) and serum amyloid protein A (SAA), was covalently bound via its carboxyl-terminal end to the carrier-protein keyhole limpet haemocyanin. The complex was injected subcutaneously into ten rabbits. All rabbits produced antisera which, unabsorbed, were specific for AA and SAA. The antisera and their isolated peptide specific antibodies were performance-tested and found to be excellent for demonstration of AA and SAA in immunoblotting and immunohistochemical techniques but unsuitable for immunoprecipitation. Since it is difficult to produce AA- and SAA-specific antisera by procedures earlier described and commercial supplies of good such reagents are unavailable, the easy production of sequence-specific such antisera will facilitate more extended studies of the corresponding antigens for diagnostic and scientific purposes.

Amino Acid Sequence↗
PubMed1978

Antigenic difference between serum amyloid protein SSA and its low molecular weight derivative SAAL revealed by an anti-amyloid A antiserum at different temperatures.

Serum amyloid protein SAA and its low molecular weight derivate SAAL have been compared in immunodiffusion with an antiserum to amyloid A at different temperatures. At room temperature or at 37 degree C SAAL and SAA did precipitate with anti-AA forming a line of identity. At 4 degrees C, however, only SAAL did react with anti AA. Experiments are described which show that the SAA-derivative SAAL has AA-related antigenic determinants exposed whereas these determinants are hidden in the parent SAA and are only exhibited as result of an unknown temperature-dependent process. Therefore, SAAL can also be distinguished from SAA by the availability of AA-related antigenic determinants for anti-AA antibodies at 4 degrees C.

Amyloid↗
PubMed1998

Amyloid beta protein is internalized selectively by hippocampal field CA1 and causes neurons to accumulate amyloidogenic carboxyterminal fragments of the amyloid precursor protein.

A critical issue concerning Alzheimer's disease is its selectivity, which leads to cellular degeneration in certain brain areas but not in others, and whether this pathogenic selectivity involves products of the amyloid precursor protein (APP). Here, we show that the amyloid beta protein Abeta1-42 is accumulated gradually and is retained intact by field CA1, but not by other subdivisions, of organotypic hippocampal slice cultures. In contrast, the slightly shorter Abeta1-40 peptide was not sequestered selectively. Sequestration of Abeta1-42 was followed by the build-up of carboxyterminal fragments of the endogenous precursor protein that were identified by immunoprecipitation. Unlike the peptide uptake, this induction appeared to be stochastic at the cellular level. In addition, the APP fragments were distributed more broadly within the CA1 pyramidal neurons than the sequestered Abeta1-42, and they appeared to be localized to synaptic terminals in the molecular layer of the dentate gyrus and in the stratum lacunosum-moleculare of the subfield CA3. Concentrations of synaptophysin, a presynaptic marker, decreased as the number of neurons producing amyloidogenic species increased. These results indicate that exogenous Abeta1-42 sets into motion a sequence that involves 1) selective uptake of the peptide by vulnerable cells at risk in Alzheimer's disease, 2) markedly enhanced production of amyloidogenic precursor material, and 3) slow deterioration of central synapses.

Amyloid beta-Peptides↗
PubMed1996

Amyloid precursor protein truncated at any of the gamma-secretase sites is not cleaved to beta-amyloid.

beta A4 secretion occurs upon processing of amyloid protein precursor (APP) by beta-secretase (N-terminus of beta A4) and gamma-secretase (C-terminus). To determine the sequence of these activities and the processing intermediate of beta A4, we expressed several truncated APP molecules in human HEK-293 cells. Immunofluorescence and biotinylation studies indicated that full-length APP or APP lacking the cytosolic domain both were located intracellularly, associated with the cell surface and secreted. APPs truncated after amino acid 40, 42, or 43 of beta A4 were not inserted into cell membranes, were found intracellularly but not on the cell surface, and were efficiently secreted into the culture medium. The secretion of APP truncated at amino acid 40 of beta A4 occurred without proteolytic processing. Neither beta A4 nor P3 (the product of the alpha-secretase) was secreted from any of the APP molecules truncated at the gamma-secretase sites. In sharp contrast to this, when the C-terminal 100 amino acids of APP were expressed (APP truncated at the N-terminus of beta A4), a robust beta A4 secretion was observed. Thus, the C-terminal fragment of APP produced by beta-secretase activity is likely to be the processing intermediate of beta A4.

Amino Acid Sequence↗
PubMed2006

Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity.

Small heat shock proteins Hsp20 and HspB2/B3 co-localize with Abeta deposition in senile plaques and cerebral amyloid angiopathy in Alzheimer's disease brains, respectively. It was the aim of our study to investigate if these and other sHsps bind to wild-type Abeta1-42 or the more toxic Abeta1-40 carrying the 'Dutch' mutation (22Glu-->Gln) (D-Abeta1-40), affect Abeta aggregation and thereby influence Abeta cytotoxicity. Binding affinity between sHsps and Abeta was investigated by surface plasmon resonance. Abeta aggregation was studied by using circular dichroism spectroscopy and electron microscopy. Furthermore, we used cultured cerebrovascular cells to investigate the effects of sHsps on Abeta-mediated cytotoxicity. Hsp20, Hsp27 and alphaB-crystallin, but not HspB2/B3, bound to Abeta (both D-Abeta1-40 and Abeta1-42) and reduced or completely inhibited aggregation of D-Abeta1-40 into mature fibrils but did not affect Abeta1-42 aggregation. Furthermore, these sHsps were effective inhibitors of the cerebrovascular toxicity of Abeta (both D-Abeta1-40 and Abeta1-42) in vitro. Binding affinity of the sHsps to D-Abeta1-40 correlated to the degree of inhibition of Abeta-mediated cytotoxicity and the potential to reduce Abeta beta-sheet and fibril formation. With Abeta1-42, a similar correlation between binding affinity and cytotoxicity was observed, but not with its aggregation state. In conclusion, sHsps may regulate Abeta aggregation and serve as antagonists of the biological action of Abeta, but the extent of their interaction depends on the type of sHsp and Abeta peptide.

Alzheimer Disease↗
PubMed2001

Three novel alternatively spliced isoforms of the human beta-site amyloid precursor protein cleaving enzyme (BACE) and their effect on amyloid beta-peptide production.

Three novel alternatively spliced transcripts of the beta-site amyloid precursor protein cleaving enzyme (BACE) were cloned from human brain. Alternative splicing of the RNA occurs at an internal donor in exon 3 and/or an internal acceptor in exon 4. The splicing events lead to a deletion of 25 (BACE-I-476), 44 (BACE-I-457) and 69 (BACE-I-432) amino acids and the latter two caused the loss of two of four N-linked glycosylation sites. Although the mature form of BACE-501 was resistant to endoglycosidase H treatment, glycosylated forms of BACE-I-457 and BACE-I-476 were sensitive. This result suggests that BACE-I-457 and BACE-I-476 underwent different post-translational modifications. Moreover, the beta-secretase activity of BACE-I-457 and BACE-I-476 was significantly weaker than that of BACE-501. Thus, these isoforms may contribute to a physiological function of BACE.

Alternative Splicing↗
PubMed2000

BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.

Production of amyloid-beta protein (Abeta) is initiated by a beta-secretase that cleaves the Abeta precursor protein (APP) at the N terminus of Abeta (the beta site). A recently identified aspartyl protease, BACE, cleaves the beta site and at residue 11 within the Abeta region of APP. Here we show that BACE2, a BACE homolog, cleaves at the beta site and more efficiently at a different site within Abeta. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases Abeta production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within Abeta by both enzymes. These data suggest that BACE2 contributes to Abeta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.

Alzheimer Disease↗