scholarly journals Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ivana Slamova ◽  
Rozita Adib ◽  
Stephan Ellmerich ◽  
Michal R. Golos ◽  
Janet A. Gilbertson ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Plasmin Activity ◽  
Transthyretin Amyloidosis ◽  
In Vivo Models ◽  
Transgenic Expression ◽  
Attr Amyloidosis ◽  
Amyloid Deposits

AbstractCardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTRS52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α2-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.

scholarly journals Amyloid deposition in granuloma of tuberculosis patients: A pilot study

2021 ◽  
Author(s):  
Shreya Ghosh ◽  
Akansha Garg ◽  
Chayanika Kala ◽  
Ashwani Kumar Thakur
Keyword(s):  
Serum Amyloid A ◽  
Amyloid Deposition ◽  
Serum Amyloid ◽  
Secondary Amyloidosis ◽  
Amyloid Formation ◽  
Tuberculosis Patients ◽  
Amyloid A ◽  
Inflammatory Conditions ◽  
Amyloid Deposits ◽  
Serum Amyloid A Protein

AbstractThe formation of granuloma is one of the characteristic feature of tuberculosis. Besides, rise in the concentration of acute phase response proteins mainly serum amyloid A is the indicator for chronic inflammation associated with tuberculosis. Serum amyloid A drives secondary amyloidosis in tuberculosis and other chronic inflammatory conditions. The linkage between serum amyloid A (SAA) protein and amyloid deposition site is not well understood in tuberculosis and other chronic inflammatory conditions. We hypothesized that granuloma could be a potential site for amyloid deposition because of the presence of serum amyloid A protein and proteases that cleave SAA and trigger amyloid formation. Based on this hypothesis, for the first time we have shown the presence of amyloid deposits in the granuloma of tuberculosis patients using the gold standard, Congo red dye staining.

Light Microscopic, Immunohistochemical, and Electron Microscopic Features of Amyloid Arthropathy in Chickens

1997 ◽  
Vol 34 (4) ◽  
pp. 271-278 ◽  
Author(s):  
N. H. M. T. Peperkamp ◽  
W. J. M. Landman ◽  
P. C. J. Tooten ◽  
A. Ultee ◽  
W. F. Voorhout ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Enterococcus Faecalis ◽  
Amyloid Fibrils ◽  
Superficial Layer ◽  
Immunogold Electron Microscopy ◽  
Amyloid Formation ◽  
Electron Microscopic ◽  
Amyloid A ◽  
Amyloid Deposits ◽  
Amyloid Arthropathy

Amyloid arthropathy has been recently recognized as a spontaneous syndrome in chickens. Predominantly, femorotibial and tarsometatarsal joints were affected, showing (peri) articular orange amyloid deposits. Immunohistochemical evaluation revealed the amyloid to be of the reactive type. Induction of amyloid arthropathy in chickens was carried out using a single intravenous injection of Enterococcus faecalis cultures. In the naturally occurring and the induced cases, amyloid deposits were found in the hypertrophic synovial villi and in the articular cartilage, particularly in the superficial layer and in the nutritional blood vessel walls. Highly sulfated glycosaminoglycans (GAGs) were found in the amyloid deposits. Ultrastructurally, bundles of amyloid fibrils were seen in invaginations of synoviocytes and chondrocytes. Immunogold electron microscopy failed to reveal signs of intracellular amyloid formation. The predilection site for amyloid deposition in the major leg joints of the chickens with reactive amyloid could be explained by the arthritic condition caused by Enterococcus faecalis bacteriaemia. The polyarthritis triggers hepatic acute phase protein synthesis and increases the vascular serum amyloid A (SAA) supply to the joint. Inflammatory and degenerative changes in the articular cartilage and adjoining tissues result in an increase of highly sulphated GAGs, which are considered to enhance deposition of SAA as amyloid.

Studies with Radiolabelled Serum Amyloid P Component Provide Evidence for Turnover and Regression of Amyloid Deposits In Vivo

1994 ◽  
Vol 87 (3) ◽  
pp. 289-295 ◽  
Author(s):  
Philip N. Hawkins
Keyword(s):  
Amyloid Fibrils ◽  
Specific Binding ◽  
Serum Amyloid ◽  
Poor Correlation ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

1. Quantitative scintigraphic and turnover studies, utilizing the specific binding affinity of serum amyloid P component for amyloid fibrils, have been developed as a tool for evaluating amyloid deposits in vivo. 2. Serial studies in over 300 patients have shown characteristic, diagnostic tissue distributions of amyloid in different types of amyloidosis. There is generally a poor correlation between quantity of amyloid and associated organ dysfunction. 3. Contrary to previous expectations, regression of amyloid has been demonstrated systematically for the first time: AA, AL and variant transthyretin-associated amyloid deposits often regress rapidly, and sometimes completely, if the supply of fibril protein precursors is substantially reduced.

scholarly journals Amylin, Aβ42, and Amyloid in Varicella Zoster Virus Vasculopathy Cerebrospinal Fluid and Infected Vascular Cells

2020 ◽  
Author(s):  
Andrew N Bubak ◽  
Cheryl Beseler ◽  
Christina N Como ◽  
Christina M Coughlan ◽  
Noah R Johnson ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Varicella Zoster Virus ◽  
Amyloid Fibrils ◽  
Central Nervous System Infection ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Varicella Zoster ◽  
Arterial Inflammation ◽  
Amyloidogenic Peptides ◽  
Interfering Rna

Abstract Background Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid. Methods Aβ peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin’s function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated. Results Compared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. Intracellular amylin, Aβ42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA. Conclusions VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.

scholarly journals A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Daniele Peterle ◽  
Giulia Pontarollo ◽  
Stefano Spada ◽  
Paola Brun ◽  
Luana Palazzi ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Human Plasma ◽  
Amyloid Fibrils ◽  
Wild Type ◽  
Senile Systemic Amyloidosis ◽  
Amyloid Deposits ◽  
Gut Mucosa ◽  
Standard Composition ◽  
Human Wild Type

AbstractAggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the protease(s) responsible for amyloidogenic fragments generation in vivo is(are) still elusive. Here, we show that subtilisin secreted from Bacillus subtilis, a gut microbiota commensal bacterium, translocates across a simulated intestinal epithelium and cleaves hTTR both in solution and human plasma, generating the amyloidogenic fragment hTTR(59–127), which is also found in SSA amyloids in vivo. To the best of our knowledge, these findings highlight a novel pathogenic mechanism for SSA whereby increased permeability of the gut mucosa, as often occurs in elderly people, allows subtilisin (and perhaps other yet unidentified bacterial proteases) to reach the bloodstream and trigger generation of hTTR fragments, acting as seeding nuclei for preferential amyloid fibrils deposition in the heart.

scholarly journals Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

2017 ◽  
Vol 11 ◽  
pp. 117954681773032 ◽  
Author(s):  
Marla B Sultan ◽  
Balarama Gundapaneni ◽  
Jennifer Schumacher ◽  
Jeffrey H Schwartz
Keyword(s):  
Disease Progression ◽  
Amyloid Fibrils ◽  
Early Stage ◽  
Heart Association ◽  
Analysis Data ◽  
Amyloid Formation ◽  
Functional Classification ◽  
Wild Type ◽  
Open Label ◽  
Transthyretin Amyloidosis

Background: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation. Methods: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. Results: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients ( P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification ( P = .0262). Conclusions: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. Trial Registration: ClinicalTrials.gov, NCT00694161.

scholarly journals BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo

2005 ◽  
Vol 168 (2) ◽  
pp. 291-302 ◽  
Author(s):  
Edward B. Lee ◽  
Bin Zhang ◽  
Kangning Liu ◽  
Eric A. Greenbaum ◽  
Robert W. Doms ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Subcellular Location ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Β Amyloid ◽  
The Relationship

Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.

scholarly journals Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?

2019 ◽  
Author(s):  
Vittorio Bellotti ◽  
Alessandra Corazza ◽  
Beatrice Foglia ◽  
Erica Novo ◽  
J. Paul Simons ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Deposition ◽  
Β Cells ◽  
Islet Amyloid ◽  
Good Tool ◽  
Amyloid Deposits ◽  
Oxygen Perfusion

ABSTRACTAggregation of islet amyloid polypeptide (IAPP) and amyloid deposition in the islets of Langerhans may significantly contribute to the multifactorial pathogenic mechanisms leading to type 2 diabetes. A direct toxic effect on β-cells of oligomeric IAAP has been demonstrated in in vitro models, but the mechanism operating in vivo is still unclear. Mice models presenting amyloid deposition and glucose intolerance represent a good tool for exploring in vivo a putative mechanism of toxicity directly related to the physical expansion of the extracellular matrix by the amyloid fibrillar aggregates. Based on our hypothesis that deposition of amyloid may influence the oxygen perfusion, we have calculated that the mean distribution of oxygen partial pressure would drop by more than 50 % in the presence of amyloid deposits in the islet. This condition of hypoxia caused by the remodelling of the extracellular space may explain the metabolic abnormalities in the Langerhans islets, otherwise interpreted as pseudo-hypoxic response to IAPP oligomers.

scholarly journals Hereditary transthyretin amyloidosis overview

2020 ◽  
Author(s):  
Fiore Manganelli ◽  
Gian Maria Fabrizi ◽  
Marco Luigetti ◽  
Paola Mandich ◽  
Anna Mazzeo ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Clinical Manifestations ◽  
Missense Mutations ◽  
Presymptomatic Testing ◽  
Transthyretin Amyloidosis ◽  
Amyloid Deposits ◽  
Appropriate Treatment ◽  
History Of ◽  
Partially Unfolded ◽  
Hereditary Transthyretin Amyloidosis

AbstractHereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient’s monitoring and treatment, and from presymptomatic testing to management of carriers.

Amyloidosis

2020 ◽  
pp. 2218-2234
Author(s):  
Mark B. Pepys ◽  
Philip N. Hawkins
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Polarized Light ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Amyloidosis is the clinical condition caused by extracellular deposition of amyloid in the tissues. Amyloid deposits are composed of amyloid fibrils, abnormal insoluble protein fibres formed by misfolding of their normally soluble precursors. About 30 different proteins can form clinically or pathologically significant amyloid fibrils in vivo as a result of either acquired or hereditary abnormalities. Small, focal, clinically silent amyloid deposits in the brain, heart, seminal vesicles, and joints are a universal accompaniment of ageing. Clinically important amyloid deposits usually accumulate progressively, disrupting the structure and function of affected tissues and lead inexorably to organ failure and death. There is no licensed treatment which can specifically clear amyloid deposits, but intervention which reduces the availability of the amyloid fibril precursor proteins can arrest amyloid accumulation and may lead to amyloid regression with clinical benefit. Pathology—amyloid fibrils bind Congo red dye producing pathognomonic green birefringence when viewed in high-intensity cross-polarized light, and the protein type can be identified by immunostaining or proteomic analysis. Amyloid deposits always contain a nonfibrillar plasma glycoprotein, serum amyloid P component, the universal presence of which is the basis for use of radioisotope-labelled serum amyloid P component as a diagnostic tracer. Clinicopathological correlation—amyloid may be deposited in any tissue of the body, including blood vessels walls and connective tissue matrix; clinical manifestations are correspondingly diverse. Identification of the amyloid fibril protein is always essential for appropriate clinical management. The specific types of amyloidosis covered in this chapter are reactive systemic (AA) amyloidosis, monoclonal immunoglobulin light chain (AL) amyloidosis, and hereditary systemic amyloidoses (including familial amyloid polyneuropathy).

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