410 research outputs found
Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets
No full textOriginal Publication: Gunilla Westermark and Per Westermark, Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 528354. http://dx.doi.org/10.1155/2008/528354 Copyright: Authors</p
Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes
No full textTransthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of transthyretincontaining cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more transthyretin-reactive islet cells, including beta cells. A weak transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of transthyretin may be altered in type-2 diabetes.Original Publication: Gunilla Westermark and Per Westermark, Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 429274. http://dx.doi.org/10.1155/2008/429274 Copyright: Authors</p
Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model
No full textBackground: Mouse AA-amyloidosis is a transmissible disease by a prion-like mechanism where amyloid fibrils act by seeding. Synthetic peptides with no amyloid relationship can assemble into amyloid-like fibrils and these may have seeding capacity for amyloid proteins. Principal Findings: Several synthetic peptides, designed for nanotechnology, have been examined for their ability to produce fibrils with Congo red affinity and concomitant green birefringence, affinity for thioflavin S and to accelerate AA-amyloidosis in mice. It is shown that some amphiphilic fibril-forming peptides not only produced Congo red birefringence and showed affinity for thioflavin S, but they also shortened the lag phase for systemic AA-amyloidosis in mice when they were given intravenously at the time of inflammatory induction with silver nitride. Peptides, not forming amyloid-like fibrils, did not have such properties. Conclusions: These observations should caution researchers and those who work with synthetic peptides and their derivatives to be aware of the potential health concerns. © 2009 Westermark et al.Original Publication:P. Westermark, Katarzyna Lundmark and Gunilla Westermark, Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model, 2009, PLoS ONE, (4), 6, e6041.http://dx.doi.org/10.1371/journal.pone.000604
Amyloid Deposition in Transplanted Human Pancreatic Islets : A Conceivable Cause of Their Long-Term Failure
No full textFollowing the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.Original Publication:Arne Andersson, Sara Bohman, L A Hakan Borg, Johan Paulsson, Sebastian Schultz, Gunilla Westermark and Per Westermark, Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 562985.http://dx.doi.org/10.1155/2008/562985Copyright: Author
Further Evidence for Amyloid Deposition in Clinical Pancreatic Islet Grafts
No full textBackground. The reasons for the long-term complete or partial loss of islet graft function are unknown, but there areobviously other reasons than just pure allogeneic graft rejection. Earlier studies have shown that deposition of isletamyloid polypeptide amyloid in transplanted islets may indicate a mechanism for loss of cells.Materials and Methods. Sections from liver material from four deceased islet-bearing recipients have been scrutinizedfor the presence of amyloid. Clinical data and certain aspects of the islet graft pathology of these patients have beenpublished previously.Result. With this extended histological analysis, we demonstrate the occurrence of amyloid deposits in islets transplantedinto the liver in three of four patients with type 1 diabetes.Conclusion. The finding adds evidence to the assumption that aggregation of islet amyloid polypeptide might be animportant cause of progressing -cell dysfunction in clinically transplanted islets
Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation
No full textAmyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP). Peptides were added in solubilized from (50 mu M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occurein cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.Original Publication:Johan F Paulsson, Sebastian Schultz, Martin Kohler, Ingo Leibiger, Per-Olof Berggren and Gunilla Westermark, Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 865850.http://dx.doi.org/10.1155/2008/865850Copyright: Author
Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis
No full textThe Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 610, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils.</p
Amyloid diagnosis, subcutaneous adipose tissue, immunohistochemistry and mass spectrometry
No full textLocalized AL amyloidosis: A suicidal neoplasm?
No full textAlthough AL amyloidosis usually is a systemic disease, strictly localized AL deposits are not exceptionally rare. Such case reports form a considerable body of published articles. Although both AL amyloidosis types are formed from an N-terminal segment of a monoclonal immunoglobulin light chain, a typical localized AL amyloid differs from the systemic counterpart by the morphological appearance of the amyloid, and presence of clonal plasma cells and of giant cells. In this article it is pointed out that localized AL amyloidosis ('amyloidoma') represents a true plasma cell neoplasm and not a pseudotumor. The pathogenesis of localized AL amyloidosis may differ from that of the systemic type, a suggestion underlined by the fact that localized AL amyloidosis of kappa type is as common as that of lambda origin, in contrast to the systemic form where lambda chains constitute the overwhelming majority of cases. It is suggested that oligomeric assemblies of the produced immunoglobulin light chain are toxic to plasma cells, which in this way commit suicide.</p
Further evidence for amyloid deposition in clinical pancreatic islet grafts
No full textBackground. The reasons for the long-term complete or partial loss of islet graft function are unknown, but there are obviously other reasons than just pure allogeneic graft rejection. Earlier studies have shown that deposition of islet amyloid polypeptide amyloid in transplanted islets may indicate a mechanism for loss of β cells. Materials and Methods. Sections from liver material from four deceased islet-bearing recipients have been scrutinized for the presence of amyloid. Clinical data and certain aspects of the islet graft pathology of these patients have been published previously. RESULT.: With this extended histological analysis, we demonstrate the occurrence of amyloid deposits in islets transplanted into the liver in three of four patients with type 1 diabetes. Conclusion. The finding adds evidence to the assumption that aggregation of islet amyloid polypeptide might be an important cause of progressing β-cell dysfunction in clinically transplanted islets
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