| 1. |
- Jurgens, Catherine A., et al.
(author)
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beta-Cell Loss and beta-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition
- 2011
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 178:6, s. 2632-2640
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Journal article (peer-reviewed)abstract
- Amyloid deposition and reduced beta-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased beta-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased beta-cell area quantified on histological sections is correlated with increased beta-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 +/- 2 and 70 +/- 4 islets/subject, respectively). Amyloid and beta cells were visualized by thioflavin S and insulin inununolabeling. Apoptotic beta cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased beta-cell area, and increased beta-cell apoptosis, as expected. There was a strong inverse correlation between beta-cell area and amyloid deposition (r = -0.42, P < 0.001). beta-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had beta-cell area equivalent to islets from control subjects. Increased amyloid 'deposition was associated with beta-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased beta-cell area and increased beta-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased beta-cell mass that characterizes type 2 diabetes.
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| 2. |
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| 3. |
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| 4. |
- Sjölander, Daniel, et al.
(author)
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Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid
- 2014
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Other publication (other academic/artistic)abstract
- Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Most systemic amyloidosis are progressive and lethal. Disease specific therapy depends on the identification of the offending proteins. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL, and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. Screening of 114 amyloid containing tissues derived from §07 verified (Congo red birefringence and immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. H-FTAA staining can be utilized as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. It was also revealed that within 5 of 15 age matched Congo red negative control samples h-FTAA detects microdeposits of amyloid-like protein aggregates in liver and kidney. The results emphasize the potential of the dye for detection of prodromal amyloidosis as well as for discovery of novel amyloid-like protein aggregates in humans.
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| 5. |
- Westermark, Gunilla T., et al.
(author)
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Further Evidence for Amyloid Deposition in Clinical Pancreatic Islet Grafts
- 2012
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 93:2, s. 219-223
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Journal article (peer-reviewed)abstract
- BACKGROUND: 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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| 6. |
- Westermark, Gunilla T., et al.
(author)
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Islet Amyloid Polypeptide and Diabetes
- 2013
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In: Current protein and peptide science. - : Bentham Science Publishers Ltd.. - 1389-2037 .- 1875-5550. ; 14:4, s. 330-337
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Research review (peer-reviewed)abstract
- Islet amyloid polypeptide (IAPP, amylin) is a 37 amino acid residue hormone expressed mainly by pancreatic islet beta cells and to less extent by some gastrointestinal endocrine cells and by certain regions in central nervous system. In experimental systems a number of different effects have been ascribed to IAPP but the in vivo importance of many of them is still unknown. At least effects on the central nervous system and on endocrine pancreatic cells are likely to be physiologically relevant. In these tissues calcitonin receptors and receptor activity-modifying proteins (RAMPs) 1 and 3, creating high affinity IAPP receptors have been identified. How expression of the components of these complexes are regulated and how further signaling is conducted are more or less unknown. IAPP is most well-known for its ability to aggregate into amyloid fibrils in islets of Langerhans in association with type 2 diabetes leading to loss of beta cells. In addition, amyloid is deposited between endocrine cells and between such cells and capillaries and most likely disturbs important interactions between the cells. How IAPP receptor complexes are affected by the amyloid formation process or by amyloid itself, or vice versa, are completely unknown.
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| 7. |
- Westermark, Gunilla T., et al.
(author)
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Localized amyloids important in diseases outside the brain : lessons from the islets of Langerhans and the thoracic aorta
- 2011
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In: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 278:20, s. 3918-3929
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Research review (peer-reviewed)abstract
- It has long been understood that amyloids can be lethal in systemic diseases. More recently, it has been accepted that local cerebral aggregation of the small peptide A beta is involved in the pathogenesis of Alzheimer's disease. Protein aggregation, with the generation of small amyloid deposits in specific organs, also occurs outside the central nervous system and often is associated with increased cell death. In this review, we discuss two lesser known but common localized amyloid fibril-forming proteins: the polypeptide hormone islet amyloid polypeptide (IAPP) and the lactadherin-derived peptide medin. IAPP aggregates and induces the depletion of islet beta-cells in type 2 diabetes and in islets transplanted into type 1 diabetic subjects. Initial amyloid deposition occurs intracellularly and parts of this amyloid consist of proIAPP. Medin derived from lactadherin expressed by smooth muscle cells aggregates into amyloid in certain arteries, particularly the thoracic aortic media layer, and may have a role in the generation of the potentially lethal conditions of thoracic aortic aneurysm and dissection.
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| 8. |
- Westermark, Gunilla T., et al.
(author)
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Prion-like aggregates : infectious agents in human disease
- 2010
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In: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914 .- 1471-499X. ; 16:11, s. 501-507
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Research review (peer-reviewed)abstract
- According to the 'protein only hypothesis', Creutzfeldt- Jakob disease and other prion disorders are transmissible by misfolded and aggregaled prion proteins that act as templates for the misfolding of the same protein in the recipient. The misfolding and aggregation of the prion protein are akin to the genesis of amyloid fibrils formed by several human and animal proteins associated with more common diseases. Two murine forms of amyloidosis, including a model of human AA amyloidosis, are transmissible. Here, we explore the possibility that human prion diseases and more common maladies associated with amyloid deposits might be transmissible by seeding or perhaps even by crossing species barriers.
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| 9. |
- Westermark, Per, et al.
(author)
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Islet amyloid polypeptide, islet amyloid, and diabetes mellitus
- 2011
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In: Physiological Reviews. - : American Physiological Society. - 0031-9333 .- 1522-1210. ; 91:3, s. 795-826
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Research review (peer-reviewed)abstract
- Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of beta-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of beta-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.
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| 10. |
- Westermark, Per, et al.
(author)
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Transthyretin-derived amyloidosis : Probably a common cause of lumbar spinal stenosis
- 2014
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 119:3, s. 223-228
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Journal article (peer-reviewed)abstract
- Background.Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs.Results. We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA.Conclusion. We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.
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| 11. |
- Caballero, Francisco, et al.
(author)
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Birth and Death of Human beta-Cells in Pancreases From Cadaver Donors, Autopsies, Surgical Specimens, and Islets Transplanted Into Mice
- 2014
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In: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 23:2, s. 139-151
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Journal article (peer-reviewed)abstract
- There is great interest in the potential of the human endocrine pancreas for regeneration by beta-cell replication or neogenesis. Our aim was to explore this potential in adult human pancreases and in both islet and exocrine tissue transplanted into mice. The design was to examine pancreases obtained from cadaver donors, autopsies, and fresh surgical specimens and compare these findings with those obtained from islet and duct tissue grafted into the kidney. Islets and exocrine tissue were transplanted into normoglycemic ICR-SCID mice and studied 4 and 14 weeks later. beta-Cell replication, as assessed by double staining for insulin and Ki67, was 0.22 +/- 0.03% at 4 weeks and 0.13 +/- 0.03% at 14 weeks. In contrast, no evidence of beta-cell replication could be found in 11 cadaver donor and 10 autopsy pancreases. However, Ki67 staining of beta-cells in frozen sections obtained at surgery was comparable to that found in transplanted islets. Evidence for neogenesis in transplanted pancreatic exocrine tissue was supported by finding beta-cells within the duct epithelium and the presence of cells double stained for insulin and cytokeratin 19 (CK19). However, beta-cells within the ducts never constituted more than 1% of the CK19-positive cells. With confocal microscopy, 7 of 12 examined cells expressed both markers, consistent with a neogeneic process. Mice with grafts containing islet or exocrine tissue were treated with various combinations of exendin-4, gastrin, and epidermal growth factor; none increased beta-cell replication or stimulated neogenesis. In summary, human beta-cells replicate at a low level in islets transplanted into mice and in surgical pancreatic frozen sections, but rarely in cadaver donor or autopsy pancreases. The absence of beta-cell replication in many adult cadaver or autopsy pancreases could, in part, be an artifact of the postmortem state. Thus, it appears that adult human beta-cells maintain a low level of turnover through replication and neogenesis.
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| 12. |
- Dahlqvist, Johanna, 1979-, et al.
(author)
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Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism
- 2012
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In: Archives of Dermatological Research. - : Springer Science and Business Media LLC. - 0340-3696 .- 1432-069X. ; 304:5, s. 377-386
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Journal article (peer-reviewed)abstract
- Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.
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| 13. |
- Kieninger, Barbara, et al.
(author)
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PTAA and B10 : new approaches to amyloid detection in tissue-evaluation of amyloid detection in tissue with a conjugated polyelectrolyte and a fibril-specific antibody fragment
- 2011
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In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 18:2, s. 47-52
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Journal article (peer-reviewed)abstract
- Methods: aEuro integral We compared the amyloid detection of PTAA and B10 to Congo red in 106 amyloid-containing tissue biopsies of diverse anatomical and precursor origin by evaluating the accordance in four grades (grade 0: no staining, grade 1: staining of < 33%% of the amyloid deposits, grade 2: 33--66%% and grade 3: aEuroS > 66%%). Results: aEuro integral PTAA showed grade 2--3 staining in 57 (54%%) cases, while B10 presented this accordance in only 25 (24%%) tissue biopsies. Grade 1 staining was found in 11 (10%%) samples with PTAA and in 62 (58%%) cases with B10. No staining at all (grade 0) occurred in 38 (36%%) biopsies when using PTAA and in 19 (18%%) cases when using B10. Conclusion: aEuro integral Although conformation-sensitive detection seemed promising, PTAA and B10 stain only a fraction of the examined amyloid samples when using routine surgical pathology settings. This study emphasises the necessity of having optimised pre-analytical protocols for recovery, storage and handling of samples if these novel amyloid ligands are to be used in routine diagnosis of amyloid.
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| 14. |
- Lundmark, Katarzyna, et al.
(author)
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Depletion of Spleen Macrophages Delays AA Amyloid Development: A Study Performed in the Rapid Mouse Model of AA Amyloidosis
- 2013
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:11, s. e79104-
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Journal article (peer-reviewed)abstract
- AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM), marginal zone macrophages (MZM), metallophilic marginal zone macrophages (MMZM). MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.
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| 15. |
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| 16. |
- Nyström, Sofia N., et al.
(author)
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AA-Amyloid is cleared by endogenous immunological mechanisms
- 2012
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In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 19:3, s. 138-145
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Journal article (peer-reviewed)abstract
- Reactive amyloidosis is a complication to longstanding inflammatory diseases.Protein amyloid A (AA), an N-terminal fragment of the acute phase protein serumamyloid A, undergoes conformational changes and is deposited as amyloid in tissue.AA-amyloidosis is reversible and reduction of amyloid mass has been reported as theinflammation ceases. Not much is known about the endogenous factors thatcontribute to amyloid resolution. Herein, we describe the dynamics of amyloiddegradation in experimental murine AA-amyloidosis and show that amyloiddegradation depends on macrophages and antibody formation. AA-amyloidosis wasinduced in mice and resolution of amyloid was monitored over time by histologicaltechniques. Internalized amyloid was present in macrophages that appeared at siteof deposition. At 9 months, when virtually all amyloid was cleared, amyloidosis wasre-induced in one group of animals by a single silver nitrate injection. This causedeposition of excessive amounts of amyloid, and indicate that even thoughundetectable the amyloid reseed in the body and can there act as amyloid enhancingfactor. Antibodies directed against protein AA were detected in animals duringamyloid clearance by ELISA-technique. Passive immunization with an amyloidspecific monoclonal antibody, produced by a B-cell clone recovered from an animalwith advanced AA-amyloidosis, diminish amyloid deposits in murine AA-amyloidosis.Immunoglobulins co-localize with amyloid deposits and can contribute to amyloiddegradation by Fc-receptor mediated phagocytosis.
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| 17. |
- Paulsson, Johan, et al.
(author)
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High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus
- 2014
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:3, s. 0093053-
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Journal article (peer-reviewed)abstract
- Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.
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| 18. |
- Rönnback, Annica, et al.
(author)
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Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions
- 2012
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:4
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Journal article (peer-reviewed)abstract
- The Arctic APP mutation (E693G) within the amyloid beta (A beta) domain of amyloid precursor protein (APP) leads to dementia with clinical features similar to Alzheimer's disease (AD), which is believed to be mediated via increased formation of protofibrils. We have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human amyloid precursor protein with the Arctic mutation (hAPParc), showing mild amyloid pathology with a relatively late onset. Here we performed a detailed analysis of the spatiotemporal progression of neuropathology in homozygous TgAPParc, focusing on intracellular A beta and diffuse A beta aggregates rather than amyloid plaques. We show that the neuropathology in homozygous TgAPParc mice starts with intracellular A beta aggregates, which is followed by diffuse extracellular A beta deposits in subiculum that later expands to brain regions receiving neuronal projections from regions already affected. Together this suggests that the pathology in TgAPParc mice affects interconnected brain regions and may represent a valuable tool to study the spread and progression of neuropathology in Alzheimer's disease.
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| 19. |
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| 20. |
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| 21. |
- Sjölander, Jonatan, et al.
(author)
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Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation.
- 2012
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In: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 287:14, s. 10824-10833
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Journal article (peer-reviewed)abstract
- Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid plays a critical role in β-cell death in type 2 diabetic patients. Since Aβ-fibrils in Alzheimer's disease activate the complement system, we have here investigated specific interactions between IAPP and complement factors. IAPP fibrils triggered limited activation of complement in vitro, involving both the classical and the alternative pathways. Direct binding assays confirmed that IAPP fibrils interact with globular head domains of complement initiator C1q. Furthermore, IAPP also bound complement inhibitors factor H and C4b-binding protein (C4BP). Recombinant C4BP mutants were used to show that complement control protein (CCP) domains 8 and 2 of the α-chain were responsible for the strong, hydrophobic binding of C4BP to IAPP. Immunostaining of pancreatic sections from type 2 diabetic patients revealed the presence of complement factors in the islets and varying degree of co-localization between IAPP fibrils and C1q, C3d as well as C4BP and FH but not membrane attack complex. Furthermore, C4BP enhanced formation of IAPP fibrils in vitro. We conclude that C4BP binds to IAPP thereby limiting complement activation and may be enhancing formation of IAPP fibrils from cytotoxic oligomers.
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| 22. |
- Sponarova, Jana, et al.
(author)
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Efficient Amyloid A Clearance in the Absence of Immunoglobulins and Complement Factors
- 2013
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:4, s. 1297-1307
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Journal article (peer-reviewed)abstract
- Amyloid A amyloidosis is a protein misfolding disease characterized by deposition of extracellular aggregates derived from the acute-phase reactant serum amyloid A protein. If untreated, amyloid A amyloidosis leads to irreversible damage of various organs, including the kidneys, liver, and heart. Amyloid A deposits regress upon reduction of serum amyloid A concentration, indicating that the amyloid can be efficiently cleared by natural mechanisms. Clearance was proposed to be mediated by humoral immune responses to amyloid. Here, we report that amyloid clearance in mice Lacking complement factors 3 and 4 (C3C4(-/-)) was equally efficient as in wild-type mice (C57BL/6), and was only slightly delayed in agammaglobulinemic mice (J(H-/-)). Hence, antibodies or complement factors are not necessary for natural amyloid clearance, implying the existence of alternative physiological pathways for amyloid removal.
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| 23. |
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