The age related amyloids: a growing family of unique biochemical substances.
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Biomedical subjects
P Westermark
Publications and source records attributed to P Westermark.
Diagnosing amyloidosis.
Diagnosis of amyloidosis still relies on tissue biopsy for microscopic examination. Biopsy from a symptom-giving organ may be used but more often an easily available tissue which is affected in most forms of systemic amyloidosis is utilized. Rectal biopsy has its place but a fine needle aspiration biopsy of subcutaneous adipose tissue offers a safe and more convenient alternative. With increasing knowledge about the chemical nature, prognosis and treatment of the different systemic amyloidoses there is an increasing demand of exact chemical typing of amyloid deposits. This typing can be performed immunologically on tissue biopsies, e.g. from subcutaneous adipose tissue, by several different methods. The distribution of amyloid in the body and the therapeutic effects can be monitored by scintigraphy after administration of radiolabelled amyloid P-component.
Adipose Tissue↗
Islet amyloid polypeptide (amylin) is expressed in sensory neurons.
Islet amyloid polypeptide (IAPP) or amylin is a hormone candidate predominantly expressed in insulin cells. A role for IAPP in the regulation of glucose homeostasis and the development of non-insulin-dependent diabetes mellitus has been proposed. IAPP is structurally related to the sensory neuropeptide calcitonin gene-related peptide. In the present study, using in situ hybridization, immunocytochemistry, and immunochemistry, the expression of IAPP in sensory neurons in the rat was investigated. IAPP was expressed in a population of small- to medium-sized nerve cell bodies in dorsal root ganglia from all levels and in the jugular-nodose and trigeminal ganglion; IAPP-expressing nerve cell bodies constituted a subpopulation of those expressing calcitonin gene-related peptide. In addition, IAPP-like immunoreactivity occurred in nerve cell bodies storing substance P and pituitary adenylate cyclase-activating polypeptide. IAPP-immunoreactive nerve fibers were encountered in the dorsal horns of the spinal cord, and to a lesser extent in peripheral tissues receiving sensory innervation; IAPP-immunoreactive fibers constituted a subpopulation of those containing calcitonin gene-related peptide and/or substance P. The immunochemical determinations demonstrated a low level of IAPP-like immunoreactivity in the dorsal root ganglia and spinal cord, which chromatographically coeluted with authentic rat IAPP. We conclude that IAPP is expressed in sensory neurons, thus being a novel sensory neuropeptide candidate for which a physiological role remains to be identified.
Amyloid↗
Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis.
BACKGROUND: In many different forms of amyloidosis, transthyretin (TTR) comprises the major amyloid fibril protein. In the familial forms, various TTR mutations are linked to disease. This study was designed to characterize the components of the TTR-derived amyloid fibril protein in senile systemic amyloidosis and to determine whether any mutation in the TTR gene was present. EXPERIMENTAL DESIGN: Heart tissues from two patients with advanced senile systemic amyloidosis were studied. Amyloid fibrils were extracted and the amyloid fibril protein purified. The relationship between full-length and fragmented TTR and the amino acid sequence of the TTR were determined. The TTR gene was studied by single-strand conformation polymorphism analysis or direct sequencing. RESULTS: In both cases, the amyloid deposits contained full-length TTR and a complex mixture of TTR fragments. The fragments, most of which had their N-termini at positions 46-52, predominated. No amino acid substitution was identified. The N-terminal fragment (1-45) was not identified in either patient. In each case, the four exons of the TTR gene were of normal sequence. CONCLUSIONS: In familial amyloidosis resulting from deposition of TTR Met 30 (Swedish-type familial amyloidosis), full-length TTR molecules (some mutant) usually predominate, and TTR fragments lacking three of the eight beta-strands (nonmutant) form a major part of the fibril in senile systemic amyloidosis. This may indicate a difference in the fibrillogenesis between these two forms of TTR-derived amyloidosis. We propose that the name senile systemic amyloidosis be used only for normal-sequence TTR amyloidosis occurring in advanced age.
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Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques.
Amyloid deposits in the aortic intima are very common in association with atherosclerosis and aging. In the present study, a major fibril protein purified from amyloid present in human atherosclerotic plaques was shown to be a 69-amino acid N-terminal fragment of apolipoprotein AI. Although senile form of localized apolipoprotein AI-derived amyloidosis has recently been documented in pulmonary vessels of dogs, this is the first example of a localized human amyloid derived from this apolipoprotein.
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Apolipoprotein AI-derived pulmonary vascular amyloid in aged dogs.
Our studies confirm the common occurrence of a unique form of apolipoprotein AI (apoAI)-derived vascular amyloidosis in dogs that appears to be unrelated to other disease conditions, but is associated with aging. Vascular amyloid deposits were most frequently located within the intima and media of medium-sized pulmonary arteries, and were not confirmed in any other tissues. Pulmonary vascular amyloid immunoreactive with antiserum to purified N-terminal (1-71) canine apoAI amyloid protein was demonstrated retrospectively in 12.8% of necropsied dogs (N = 243) 10 years of age or older. In a subsequent expanded 1-year prospective study of necropsied dogs (N = 231) of all ages, apoAI-derived pulmonary vascular amyloid deposits were demonstrated in 0.7% of dogs < 10 years of age and in 22% of dogs 10 years of age or older. The incidence of this form of amyloid in dogs 10 years of age or older was significantly associated with advancing age (P < 0.00001). However, significant differences regarding gender, breed, or the frequency of selected common disease conditions were not observed when the dogs with apoAI-derived amyloid were compared with control dogs. The possibility that this new form of senile apoAI-derived amyloidosis is a manifestation of an age-associated aberration in apoAI metabolism or is related to a mutant form of apoAI is the subject of ongoing investigations.
Aging↗
Amyloid formation in response to beta cell stress occurs in vitro, but not in vivo, in islets of transgenic mice expressing human islet amyloid polypeptide.
BACKGROUND: Human, but not mouse, islet amyloid polypeptide (IAPP) is amyloidogenic. Transgenic mice overexpressing human IAPP in the beta cells of the islets of Langerhans should be useful in identifying factors important for the deposition of IAPP as insoluble amyloid fibrils. MATERIALS AND METHODS: Transgenic mice expressing human IAPP were examined using several experimental models for the production of persistent hyperglycemia, as well as for the overstimulation and/or inhibition of beta cell secretion. Obesity was induced by aurothioglucose. Persistent hyperglycemia was produced by long-term administration of glucocorticosteroids or by partial pancreatectomy. Inhibition of normal beta cell exocytosis by diazoxide administration, with or without concurrent dexamethasone injections, was carried out to increase crinophagy of secretory granules. The human IAPP gene was also introduced into the ab and ob mouse models for diabetes. Finally, isolated islets cultivated in vitro at high glucose concentration were also examined. RESULTS: No amyloid deposits were found in the pancreata of any of the animals, either by light microscopy after Congo red staining or by electron microscopy after immunogold labeling with antibodies specific for human IAPP. Aurothioglucose treatment resulted in increased numbers of granules in the beta cell and the appearance of large lysosomal bodies without amyloid. However, islets from db and ob mice expressing human IAPP cultivated in vitro in the presence of glucocorticosteroid and/or growth hormone, were found to contain extracellular amyloid deposits reacting with antibodies to human IAPP. CONCLUSIONS: Oversecretion of human IAPP or increased crinophagy are not sufficient for amyloid formation. This indicates that other factors must influence amyloid deposition; one such factor may be the local clearance of IAPP.
Amyloid↗
Vulvitis granulomatosa: a cryptogenic chronic inflammatory hypertrophy of vulvar labia related to cheilitis granulomatosa and Crohn's disease.
We report the cases of two patients with vulvitis granulomatosa, a chronic inflammatory hypertrophy of the vulvar labia thought to represent the vulvar variant of cheilitis granulomatosa. One of the women later experienced recurring cheilitis granulomatosa, while the other developed intestinal Crohn's disease 6 years later. The interrelationships of vulvitis granulomatosa, cheilitis granulomatosa, and Crohn's disease are discussed.
Adult↗
Islet amyloid polypeptide stimulates cyclic AMP accumulation via the porcine calcitonin receptor.
CHO-cells stably transfected with an expression vector for the porcine calcitonin receptor were exposed to various concentrations of IAPP, CGRP or calcitonin from different species. In these, but not in untransfected cells, rat IAPP mediated cAMP accumulation at concentrations above 25 nM. This potency was three orders of magnitude lower than that of porcine calcitonin and two and four orders of magnitude lower than those of human and salmon calcitonin, respectively. Human beta-CGRP had an effect similar to rat IAPP whereas human alpha-CGRP was at least one order of magnitude less potent than rat IAPP. COS cells expressing recombinant porcine calcitonin receptors transiently or stably showed a different pattern of responses to calcitonin, IAPP and the CGRPs. In these cells, rat IAPP was as potent an inducer of cAMP as was salmon or porcine calcitonin and more potent than human calcitonin or the CGRPs. The dissociation constants for salmon calcitonin binding to the porcine calcitonin receptors on CHO and COS cells were 0.2 nM and 2.0 nM and the corresponding number of binding sites per cell were approximately 7 x 10(4) and 2 x 10(6), respectively. These results demonstrate that IAPP and CGRP can mediate signal transduction via the porcine calcitonin receptor and provide a possible explanation for the calcitonin-like effects of pharmacological levels of IAPP and CGRP administrated in vivo. The difference between CHO and COS cells in their relative response to the various ligands may relate to the difference in receptor number, post-transcriptional processing, or to dissimilarities in the signal transduction pathways between the two cell types.
Amino Acid Sequence↗
Fibrils from synthetic amyloid-related peptides enhance development of experimental AA-amyloidosis in mice.
Amyloid enhancing factor is an incompletely characterized activity of extracts from many amyloid-containing tissues and which greatly shortens the preamyloidotic phase during experimental induction of AA-amyloidosis. In this communication we show that amyloid-like fibrils made in vitro from synthetic peptides, corresponding to segments of amyloid fibril proteins, have amyloid enhancing factor-like activity. Thus, there is a possibility that amyloid enhancing factor activity depends on small fibrils serving as nucleation centers for fibril elongation.
Amino Acid Sequence↗
Islet amyloid polypeptide in patients with pancreatic cancer and diabetes.
BACKGROUND: The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. METHODS: We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. RESULTS: Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P < 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P < 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. CONCLUSIONS: Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.
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Islet amyloid polypeptide is expressed in endocrine cells of the gastric mucosa in the rat and mouse.
BACKGROUND/AIMS: Islet amyloid polypeptide (IAPP) or amylin is a novel islet hormone candidate with a suggested role in the regulation of glucose homeostasis and the pathogenesis of non-insulin dependent diabetes mellitus. Occurrence of IAPP in the gastrointestinal tract of rats and humans has also been shown. The expression of IAPP in the stomach of the rat and mouse and the possible colocalization of IAPP and known gastric hormones were investigated in this study. METHODS: In situ hybridization, immunofluorescence, and combined in situ hybridization and immunocytochemistry were used. RESULTS: IAPP messenger RNA and IAPP-like immunoreactivity were shown in the same endocrine cells in the antrum and fundus of the rat and in the antrum of the mouse. IAPP was expressed in a major population of somatostatin-immunoreactive cells as well as in small populations of gastrin- and peptide YY-immunoreactive cells. CONCLUSIONS: Our results establish the synthesis and storage of IAPP in gastric endocrine cells in the rat and mouse. The extensive colocalization of IAPP with somatostatin and to a lesser extent with gastrin and peptide YY suggests that IAPP may modulate endocrine activity in the gastric mucosa in a paracrine and/or autocrine mode.
Amyloid↗
Amyloid in basal cell carcinoma and seborrheic keratosis.
The frequency of amyloid substance was studied in two different types of skin tumours: basal cell carcinoma and seborrheic keratosis. In 9 out of 49 cases of seborrheic keratosis amyloid substance was found. In the basal cell carcinomas, 194 out of 260 cases showed amyloid deposits, a rate that is higher than that previously reported. The basal cell carcinoma material was further studied regarding the amount of amyloid, mitotic rate, degree of apoptosis and the age of the patients. There was no correlation between the amount of amyloid and the mitotic rate, or the degree of apoptosis. There was a slightly higher incidence of amyloid-positive cases among elderly patients.
Amyloid↗
Mechanisms of transthyretin amyloidogenesis. Antigenic mapping of transthyretin purified from plasma and amyloid fibrils and within in situ tissue localizations.
Transthyretin (TTR) is the major amyloid fibril protein in senile systemic amyloidosis and in several forms of familial amyloidoses. However, the internal organization of the fibrils is virtually unknown. It is not known whether the structure of the TTR molecules is substantially altered within the fibrils. In this study we used various antigenic mapping procedures to determine whether major antigenic sites differ between normal TTR, ATTR (TTR from amyloid fibrils), and in situ amyloid fibrils. Antigenic mapping was achieved using standard immunological procedures (ie, ELISA, Western blot, and immunohistochemistry), synthetic peptides of the TTR molecule, antisera against these synthetic peptides and against normal TTR, ATTR, and alkali-degraded amyloid fibrils. Our results show that the antigenic sites on normal plasma TTR include the AB loop and the CD loop. The amino acid sequences associated with these loops are present on the outside of the TTR molecule. Antiserum against beta-strand H reacted only with TTR in amyloid fibrils and ATTR but not with normal plasma TTR or TTR in the islets of Langerhans. Our results suggest that there is an altered configuration of TTR within amyloid fibrils when compared with plasma TTR.
Amino Acid Sequence↗
Human islet amyloid polypeptide transgenic mice as a model of non-insulin-dependent diabetes mellitus (NIDDM).
To model islet amyloidogenesis in NIDDM and explore the glucoregulatory role of islet amyloid polypeptide (IAPP), we have created transgenic mice containing a rat insulin-I promoter-human IAPP fusion gene. Expression of human IAPP was localized to the islets of Langerhans, anterior pituitary and brain in transgenic animals; blood IAPP levels were elevated 5-fold while fasting glucose levels remained normal. Amyloid deposits have not been detected in transgenic islets suggesting that other co-existing abnormalities in NIDDM may be required for the formation of islet amyloid. These animals provide a unique model for exploring this hypothesis and other proposed functions of IAPP.
Amyloid↗
Islet amyloid polypeptide in the rabbit and European hare: studies on its relationship to amyloidogenesis.
In this study, we determined the cDNA-predicted amino acid sequence of positions 9-31 of islet amyloid polypeptide from the rabbit and European hare. A synthetic rabbit/hare islet amyloid polypeptide 20-29 peptide was subsequently shown to be strongly fibrillogenic in vitro even though the putative amyloidogenic AILS sequence at positions 25-28 of human and cat islet amyloid polypeptide is modified in the rabbit and hare by a substitution of phenylalanine for leucine at position 27 (i.e. AIFS). Although islet amyloid polypeptide of both the rabbit and hare has an amyloidogenic sequence and is in fact amyloidogenic in vitro, the apparent lack of in vivo islet amyloidosis in rabbits and hares may be related to relatively low levels of islet amyloid polypeptide production by the islet beta cells in these species. This was supported by our findings that there is no substantial immunoreactivity in either rabbit or hare islets, and no measurable amount either in extracts of rabbit pancreases, or in rabbit plasma. This study supports the need for at least two prerequisites for the development of islet amyloidosis in vivo: an inherent fibrillogenic sequence within the islet amyloid polypeptide molecule and an adequate local concentration of islet amyloid polypeptide to promote self aggregation and formation of islet amyloid.
Amino Acid Sequence↗
Islet amyloid polypeptide: demonstration of mRNA in human pancreatic islets by in situ hybridization in islets with and without amyloid deposits.
Islet amyloid polypeptide which is normally coexpressed with insulin in beta cells, forms amyloid deposits especially in islets of Type 2 (non-insulin-dependent) diabetic subjects. Occurrence of islet amyloid is paradoxically associated with loss of islet amyloid polypeptide immunoreactivity in beta cells. The present study was undertaken to examine whether the islet amyloid polypeptide gene is expressed in islets with decreased islet amyloid polypeptide immunoreactivity. Pancreatic tissue from 14 patients, 7 with Type 2 diabetes and 7 non-diabetic, were obtained at autopsy or surgery and studied for islet amyloid polypeptide expression by in situ hybridization and for presence of insulin and islet amyloid polypeptide by immunohistochemistry. Six of the specimens from the diabetic and three of those from the non-diabetic patients had varying degrees of islet amyloid polypeptide-derived islet amyloid. Amyloid deposits were associated with decreased numbers of beta cells with islet amyloid polypeptide immunoreactivity despite an apparent normal frequency of insulin-containing cells. This discrepancy might reflect an alteration in islet amyloid polypeptide production or processing at a transcriptional or post-transcriptional level. In contrast to the varying immunohistochemical patterns, islets of all categories showed strong labelling using an islet amyloid polypeptide probe for in situ hybridization. It is concluded that islet amyloid polypeptide production is not altered at the transcriptional level. The following possibilities remain: (1) islet amyloid polypeptide production may be altered at a post-transcriptional level or (2) that islet amyloid polypeptide production is normal but the reduced immunoreactivity of the cells reflects a reduced storage of IAPP in secretory granules.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Tumour-like localized amyloid of the brain is derived from immunoglobulin light chain.
A patient is presented in whom the amyloid component of an intracerebral 'amyloidoma' has been purified and characterized by amino acid sequence analysis. The material originated from an autopsy of a 76-year-old man who 15 years earlier had been operated for an intracerebral 'amyloid tumour'. The tumour had recurred and grown to an almost walnut-sized mass in the right cerebral hemisphere. It was located in the parietal lobe close to the lateral ventricle and had a close connection to the choroid plexus. Histological examination showed large masses of amyloid surrounded by some plasma cells and a few macrophages of the foreign body type. Amino acid sequence analysis of a major fibril subunit protein showed homology with the variable region of a monoclonal lambda immunoglobulin light chain, subgroup III or IV. This shows that the amyloid in the 'tumour' was of AL type and presumably derived from local synthesis by plasma cells.
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