Pathogenetic mechanisms of amyloid A amyloidosis Simons, J. Paul; Al-Shawib, Raya; Ellmerich, Stephan ...
Proceedings of the National Academy of Sciences - PNAS,
10/2013, Letnik:
110, Številka:
40
Journal Article
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Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils ...that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.
Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid ...can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A kindred with familial amyloidosis was found to have bowel and autonomic dysfunction and the sicca syndrome from an aspartate-to-asparagine alteration at amino acid 76 of β2-microglobulin. ...Unexpectedly, this alteration promoted fibrillogenesis and tissue deposition.
Summary
We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β
2
-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β
2
-microglobulin, the affected members of this kindred had normal renal function and normal circulating β
2
-microglobulin values. The Asp76Asn β
2
-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β
2
-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β . . .
Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, ...2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1|-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.
The human pentraxin proteins, serum amyloid P component (SAP) and C‐reactive protein (CRP) are important in routine clinical diagnosis, SAP for systemic amyloidosis and CRP for monitoring the ...non‐specific acute phase response. They are also targets for novel therapies currently in development but their roles in health and disease are controversial. Thus, both for clinical use and to rigorously elucidate their functions, structurally and functionally intact, pharmaceutical grade preparations of the natural, authentic proteins are required. We report here the production from normal human donor plasma and the characterization of the first such preparations. Importantly, we demonstrate that, contrary to reports using recombinant proteins and less well characterized preparations, neither CRP nor SAP stimulate the release by human peripheral blood mononuclear cells in vitro of any TNFα, IL‐6 or IL‐8, nor does SAP cause release of IL‐1β or IL‐10. Furthermore neither of our preparations was pro‐inflammatory in mice in vivo.
The article discusses hereditary systemic amyloidosis due to Asp76Asn variant beta 2-microglobulin. The Asp76Asn variant B2-microglobulin variant was found to be thermodynamically unstable and ...remarkably fibrillogenic in vitro under physiological conditions.
The structural properties of three immunoglobulins light chains: κ SCI, responsible for light chain deposition disease (Bellotti, V., Stoppini, M., Merlini, G., Zapponi, M.C., Meloni, M.L., Banfi, G. ...and Ferri, G. (1991) Biochim. Biophys. Acta 1097, 177–182), k INC responsible for light chain amyloidosis (Ferri, G., Stoppini, M., Iadarola, P., Bellotti, V. and Merlini, G. (1989) Biochim. Biophys. Acta 995, 103–108) and the non-pathogenic κ MOS were analyzed by fluorescence spectroscopy and circular dichroism.
Comparative evaluation of the data shows that SCI and MOS have similar stability under different conditions, while the amyloid k INC behaves as a very unstable protein.
As calculated from the GdnHCl curves, the midpoint of unfolding transition was 1.35 M for SCI, 1.20 M for MOS and 0.1 M for INC. Analysis of CD spectra evidences that the three proteins conserve their conformation in the range of pH 4–8. Change in temperature at pH 4.0 produces the premature transition of INC (
T
m 40°C) with respect to SCI and MOS (
T
m 50°C). At this pH both the pathological SCI and INC light chains aggregate at a temperature of 20°C lower than the normal counterpart. The specific kidney deposition of κ SCI has been evidenced after injection of the
125I labelled light chain into mice. No deposition was detectable in the case of INC and MOS.
AL amyloidosis is caused by deposition in target tissue of amyloid fibrils constituted by monoclonal immunoglobulin light chains. The amyloidogenic plasma cells derive from a transformed memory B ...cell that can be identified by anti-idiotype monoclonal antibodies. Comparison of the primary structures of amyloidogenic and nonamyloidogenic light chains does not show any common structural motif in the amyloidogenic variants but reveals peculiar replacements which can destabilize the folding state. Reduced folding stability now appears to be a unifying property of amyloidogenic light chains. The tendency of these proteins to populate a partially unfolded intermediate state is a key event in the self-association that progresses to the formation of oligomers and fibrils. The mechanism of organ damage caused by AL amyloid deposition is not known, but clinical findings suggest that the process of amyloid fibril formation itself exerts tissue toxic effects independently of the amount of amyloid deposited. Since the disease is caused by the neoplastic expansion of the plasma cell population synthesizing the amyloidogenic light chains, the clone represents the prime therapeutic target of conventional chemotherapy and experimental immunotherapy. In common with other types of amyloidosis the therapeutic strategy can take advantage of drugs able to improve the reabsorption of the amyloid deposits or able to bind and stabilize the light chain in the native-like folded state.
The N-terminal portion of apolipoprotein A-I corresponding to the first 93 residues has been identified as the main component
of apolipoprotein A-I fibrils in a form of systemic amyloidosis. We have ...been able to characterize the process of conformational
switching and fibrillogenesis in this fragment of apolipoprotein A-I purified directly from ex vivo amyloid material. The peptide exists in an unstructured form in aqueous solution at neutral pH. The acidification of the
solution provokes a collapse into a more compact, intermediate state and the transient appearance of a helical conformation
that rapidly converts to a stable, mainly β-structure in the fibrils. The transition from helical to sheet structure occurs
concomitantly with peptide self-aggregation, and fibrils are detected after 72 h. The α-helical conformation is induced by
the addition of trifluoroethanol and phospholipids. Interaction of the amyloidogenic polypeptide with phospholipids prevents
the switching from helical to β-sheet form and inhibits fibril formation. The secondary structure propensity of the apolipoprotein
A-I fragment appears poised between helix and the β-sheet. These findings reinforce the idea of a delicate balance between
natively stabilizing interactions and fatally stabilizing interactions and stress the importance of cellular localization
and environment in the maintenance of protein conformation.
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