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1
Bajic, Vladan P., Adil Salhi, Katja Lakota, Aleksandar Radovanovic, Rozaimi Razali, Lada Zivkovic, Biljana Spremo-Potparevic, et al. "DES-Amyloidoses “Amyloidoses through the looking-glass”: A knowledgebase developed for exploring and linking information related to human amyloid-related diseases." PLOS ONE 17, no. 7 (July 25, 2022): e0271737. http://dx.doi.org/10.1371/journal.pone.0271737.
Повний текст джерелаАнотація:
More than 30 types of amyloids are linked to close to 50 diseases in humans, the most prominent being Alzheimer’s disease (AD). AD is brain-related local amyloidosis, while another amyloidosis, such as AA amyloidosis, tends to be more systemic. Therefore, we need to know more about the biological entities’ influencing these amyloidosis processes. However, there is currently no support system developed specifically to handle this extraordinarily complex and demanding task. To acquire a systematic view of amyloidosis and how this may be relevant to the brain and other organs, we needed a means to explore "amyloid network systems" that may underly processes that leads to an amyloid-related disease. In this regard, we developed the DES-Amyloidoses knowledgebase (KB) to obtain fast and relevant information regarding the biological network related to amyloid proteins/peptides and amyloid-related diseases. This KB contains information obtained through text and data mining of available scientific literature and other public repositories. The information compiled into the DES-Amyloidoses system based on 19 topic-specific dictionaries resulted in 796,409 associations between terms from these dictionaries. Users can explore this information through various options, including enriched concepts, enriched pairs, and semantic similarity. We show the usefulness of the KB using an example focused on inflammasome-amyloid associations. To our knowledge, this is the only KB dedicated to human amyloid-related diseases derived primarily through literature text mining and complemented by data mining that provides a novel way of exploring information relevant to amyloidoses.
2
Wisniowski, Brendan, and Ashutosh Wechalekar. "Confirming the Diagnosis of Amyloidosis." Acta Haematologica 143, no. 4 (2020): 312–21. http://dx.doi.org/10.1159/000508022.
Повний текст джерелаАнотація:
Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many cases, death. Amyloid fibrils are derived from soluble precursor proteins, with the number of known amyloidogenic proteins increasing over time. The identity of the precursor protein often predicts the disease phenotype, although many of the amyloidoses have overlapping clinical features. Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis. Cardiac transthyretin amyloidosis, however, may be diagnosed without a biopsy provided stringent criteria are met. Where amyloid is confirmed histologically, the identity of the amyloidogenic protein must be determined, given several of the amyloidoses have disease-specific therapies. Laser capture microdissection and tandem mass spectrometry, LCM-MS, has revolutionised amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry. Here we summarise the biopsy approach to amyloidosis, as well as the non-biopsy diagnosis of cardiac transthyretin amyloidosis. Proteomic and antibody-based methods for amyloid subtyping are reviewed. Finally, an algorithm for confirming the diagnosis of amyloidosis is presented.
3
Koike, Haruki, and Masahisa Katsuno. "The Ultrastructure of Tissue Damage by Amyloid Fibrils." Molecules 26, no. 15 (July 29, 2021): 4611. http://dx.doi.org/10.3390/molecules26154611.
Повний текст джерелаАнотація:
Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.
4
Acquasaliente, Laura, and Vincenzo De Filippis. "The Role of Proteolysis in Amyloidosis." International Journal of Molecular Sciences 24, no. 1 (December 31, 2022): 699. http://dx.doi.org/10.3390/ijms24010699.
Повний текст джерелаАнотація:
Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
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Guan, Jian, Shikha Mishra, Rodney H. Falk, and Ronglih Liao. "Current perspectives on cardiac amyloidosis." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 3 (February 2012): H544—H552. http://dx.doi.org/10.1152/ajpheart.00815.2011.
Повний текст джерелаАнотація:
Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.
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Czyżewska, Emilia. "Amyloidoses – pathogenesis, classification, diagnosis." Diagnostyka Laboratoryjna 56, no. 4 (July 9, 2021): 1–13. http://dx.doi.org/10.5604/01.3001.0015.0266.
Повний текст джерелаАнотація:
Amyloidoses – also known as amyloidosis or betafibrillosis – a diverse group of diseases in which amorphous protein with a changed conformational structure is deposited extracellularly, leading to the failure of many organs. The basic classifications of amyloidoses take into account: the type of precursor protein, the division into generalized (systemic) amyloidoses, in which amyloid deposits accumulate in many organs, vessel walls and connective tissue (e.g. AL amyloidosis) and local (localized) amyloidoses – limited to only one organ (e.g. corneal amyloidosis) as well as congenital and acquired diseases. Symptoms of amyloidosis are non-specific and not very characteristic, moreover, their severity depends on the type of disease and organ involvement. The diagnosis of amyloidosis should be considered in patients with heart failure without coronary artery disease, with neuropathy, or proteinuria or hepatomegaly of unclear origin. Diagnosis of amyloidosis is based on the evaluation of tissue biopsy samples and the presence of abnormal proteins, i.e. amyloid, or on the fibrillary evaluation confirmation of the filamentous nature of amyloid deposits using electron microscopy. The next step is differential diagnosis and amyloid differential identification, which is based on immunohistochemical and immunofluorescence studies using labeled antibodies. The "gold standard" used in typing amyloidosis and identifying an amyloidogenic protein is mass spectrometry. Laboratory tests are used to assess organ involvement, which is the basis of the prognostic classification.
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Ablasser, Klemens, Nicolas Verheyen, Theresa Glantschnig, Giulio Agnetti, and Peter P. Rainer. "Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure." Current Medicinal Chemistry 26, no. 16 (August 26, 2019): 2865–78. http://dx.doi.org/10.2174/0929867325666180104153338.
Повний текст джерелаАнотація:
Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR.
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Rognoni, Paola, Giulia Mazzini, Serena Caminito, Giovanni Palladini, and Francesca Lavatelli. "Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics." Medicina 57, no. 9 (August 31, 2021): 916. http://dx.doi.org/10.3390/medicina57090916.
Повний текст джерелаАнотація:
Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.
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Khoor, Andras, and Thomas V. Colby. "Amyloidosis of the Lung." Archives of Pathology & Laboratory Medicine 141, no. 2 (February 1, 2017): 247–54. http://dx.doi.org/10.5858/arpa.2016-0102-ra.
Повний текст джерелаАнотація:
Context.—Amyloidosis is a heterogeneous group of diseases characterized by the deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. To date, 31 fibril proteins have been identified in humans, and it is now recommended that amyloidoses be named after these fibril proteins. Based on this classification scheme, the most common forms of amyloidosis include systemic AL (formerly primary), systemic AA (formerly secondary), systemic wild-type ATTR (formerly age-related or senile systemic), and systemic hereditary ATTR amyloidosis (formerly familial amyloid polyneuropathy). Three different clinicopathologic forms of amyloidosis can be seen in the lungs: diffuse alveolar-septal amyloidosis, nodular pulmonary amyloidosis, and tracheobronchial amyloidosis. Objective.—To clarify the relationship between the fibril protein–based amyloidosis classification system and the clinicopathologic forms of pulmonary amyloidosis and to provide a useful guide for diagnosing these entities for the practicing pathologist. Data Sources.—This is a narrative review based on PubMed searches and the authors' own experiences. Conclusions.—Diffuse alveolar-septal amyloidosis is usually caused by systemic AL amyloidosis, whereas nodular pulmonary amyloidosis and tracheobronchial amyloidosis usually represent localized AL amyloidosis. However, these generalized scenarios cannot always be applied to individual cases. Because the treatment options for amyloidosis are dependent on the fibril protein–based classifications and whether the process is systemic or localized, the workup of new clinically relevant cases should include amyloid subtyping (preferably with mass spectrometry–based proteomic analysis) and further clinical investigation.
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Spodzieja, Marta, Sylwia Rodziewicz-Motowidło, and Aneta Szymanska. "Hyphenated Mass Spectrometry Techniques in the Diagnosis of Amyloidosis." Current Medicinal Chemistry 26, no. 1 (March 14, 2019): 104–20. http://dx.doi.org/10.2174/0929867324666171003113019.
Повний текст джерелаАнотація:
Amyloidoses are a group of diseases caused by the extracellular deposition of proteins forming amyloid fibrils. The amyloidosis is classified according to the main protein or peptide that constitutes the amyloid fibrils. The most effective methods for the diagnosis of amyloidosis are based on mass spectrometry. Mass spectrometry enables confirmation of the identity of the protein precursor of amyloid fibrils in biological samples with very high sensitivity and specificity, which is crucial for proper amyloid typing. Due to the fact that biological samples are very complex, mass spectrometry is usually connected with techniques such as liquid chromatography or capillary electrophoresis, which enable the separation of proteins before MS analysis. Therefore mass spectrometry constitutes an important part of the so called “hyphenated techniques” combining, preferentially in-line, different analytical methods to provide comprehensive information about the studied problem. Hyphenated methods are very useful in the discovery of biomarkers in different types of amyloidosis. In systemic forms of amyloidosis, the analysis of aggregated proteins is usually performed based on the tissues obtained during a biopsy of an affected organ or a subcutaneous adipose tissue. In some cases, when the diagnostic biopsy is not possible due to the fact that amyloid fibrils are formed in organs like the brain (Alzheimer’s disease), the study of biomarkers presented in body fluids can be carried out. Currently, large-scale studies are performed to find and validate more effective biomarkers, which can be used in diagnostic procedures. We would like to present the methods connected with mass spectrometry which are used in the diagnosis of amyloidosis based on the analysis of proteins occurring in tissues, blood and cerebrospinal fluid.
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van der Hilst, J. C. H. "Recent Insights into the Pathogenesis of Type AA Amyloidosis." Scientific World JOURNAL 11 (2011): 641–50. http://dx.doi.org/10.1100/tsw.2011.64.
Повний текст джерелаАнотація:
The amyloidoses are a group of life-threatening diseases in which fibrils made of misfolded proteins are deposited in organs and tissues. The fibrils are stable, insoluble aggregates of precursor proteins that have adopted an antiparallel β-sheet structure. In type AA, or reactive, amyloidosis, the precursor protein of the fibrils is serum amyloid A (SAA). SAA is a 104-amino-acid protein that is produced in the liver in response to proinflammatory cytokines. Although the protein that is produced by the liver contains 104 amino acids, only the N-terminal 66–76 amino acids are found in amyloid fibrils. Furthermore, SAA has been shown to have an α-helical structure primarily. Thus, for SAA to be incorporated into an amyloid fibril, two processes have to occur: C-terminal cleavage and conversion into a β-sheet. Only a minority of patients with elevated SAA levels develop amyloidosis. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in SAA, and the type of autoinflammatory syndrome. In the Hyper-IgD syndrome, amyloidosis is less prevalent than in the other autoinflammatory diseases.In vitrowork has shown that the isoprenoid pathway influences amyloidogenesis by farnesylated proteins. Although many proteins contain domains that have a potential for self-aggregation, amyloidosis is only a very rare event. Heat shock proteins (HSPs) are chaperones that assist other proteins to attain, maintain, and regain a functional conformation. In this review, recent insights into the pathogenesis of amyloidosis are discussed, in addition to a new hypothesis for a role of HSPs in the pathogenesis of type AA.
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Nemshah, Yaser, Alex Clavijo, and Gyanendra Sharma. "Amyloid Heart Disease." US Cardiology Review 12, no. 2 (2018): 113. http://dx.doi.org/10.15420/usc.2018.5.1.
Повний текст джерелаАнотація:
Cardiac amyloidosis is a group of disorders that develop secondary to the deposition of misfolded proteins in the heart. It can occur in isolation or as part of a systemic disease and can be inherited or acquired. Amyloid light chain (AL) and amyloid transthyretin (ATTR) are the two main forms of amyloid proteins that can infiltrate the heart. With the increased use of advanced imaging techniques and protocols, the recognition and diagnosis of cardiac amyloidosis, especially ATTR, has become easier. New therapies intended to improve survival and quality of life in patients with cardiac amyloidosis are emerging. This article provides an up-to-date review of cardiac amyloidosis.
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ISOBE, TAKASHI. "Amyloid proteins and amyloidosis.2 Amyloidosis of AA proteins and AL proteins." Nihon Naika Gakkai Zasshi 82, no. 9 (1993): 1415–19. http://dx.doi.org/10.2169/naika.82.1415.
Повний текст джерела
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Brambilla, Francesca, Francesca Lavatelli, Dario Di Silvestre, Veronica Valentini, Rossana Rossi, Giovanni Palladini, Laura Obici, Laura Verga, Pierluigi Mauri, and Giampaolo Merlini. "Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue." Blood 119, no. 8 (February 23, 2012): 1844–47. http://dx.doi.org/10.1182/blood-2011-07-365510.
Повний текст джерелаАнотація:
Abstract Considering the important advances in treating specific types of systemic amyloidoses, unequivocal typing of amyloid deposits is now essential. Subcutaneous abdominal fat aspiration is the easiest, most common diagnostic procedure. We developed a novel, automated approach, based on Multidimensional Protein Identification Technology, for typing amyloidosis. Fat aspirates were obtained from patients with the most common systemic amyloidoses (ALλ, ALκ, transthyretin, and reactive amyloidosis), with Congo red score more than or equal to 3+, and nonaffected controls. Peptides from extracted and digested proteins were analyzed by Multidimensional Protein Identification Technology. On semiquantitative differential analysis (patients vs controls) of mass spectrometry data, specific proteins up-represented in patients were identified and used as deposit biomarkers. An algorithm was developed to classify patients according to type and abundance of amyloidogenic proteins in samples; in all cases, proteomic characterization was concordant with fibril identification by immunoelectron microscopy and consistent with clinical presentation. Our approach allows reliable amyloid classification using readily available fat aspirates.
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Picken, Maria M. "Amyloidosis—Where Are We Now and Where Are We Heading?" Archives of Pathology & Laboratory Medicine 134, no. 4 (April 1, 2010): 545–51. http://dx.doi.org/10.5858/134.4.545.
Повний текст джерелаАнотація:
Abstract Context.—Amyloidoses are disorders of diverse etiology in which deposits of abnormally folded proteins share distinctive staining properties and fibrillar ultrastructural appearance. Amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment of systemic amyloidoses the importance of an early diagnosis of amyloid, and a correct diagnosis of its type, has been realized. Objective.—To summarize current recommendations for the diagnosis of amyloidosis. Data Sources.—Presentation given at the 4th Annual Renal Pathology Society Satellite meeting in Istanbul based on discussions and recommendations formulated during an interactive diagnostic session held at the XIth International Symposium on Amyloidosis in Woods Hole, Massachusetts. Conclusions.—Congo red stain is currently the gold standard for amyloid detection and the goal is to detect amyloid early. Diagnosis of the amyloid type must be based on the identification of amyloid protein within the deposits and not solely by reliance on clinical or DNA studies. However, the latter are recommended for confirmation of the amyloid type based on evaluation of the protein in deposits. Immunohistochemistry must be performed and interpreted with caution and inconclusive results must be evaluated further using the more sophisticated methods available in referral centers. An adequate amount and quality of tissue must be available for amyloid diagnosis and typing with emphasis on the use of fresh tissue and greater use of abdominal fat biopsy. The development of new technologies underscores the need for regular review of recommendations and standards for the clinical diagnosis of amyloidosis.
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Giannini, Gabriel, and Cynthia C. Nast. "An Organ System–Based Approach to Differential Diagnosis of Amyloid Type in Surgical Pathology." Archives of Pathology & Laboratory Medicine 144, no. 3 (November 7, 2019): 379–87. http://dx.doi.org/10.5858/arpa.2018-0509-ra.
Повний текст джерелаАнотація:
Context.— Amyloidosis is an uncommon but important entity. A protein-based classification of amyloidosis defines the underlying disease process, directing clinical management and providing prognostic information. However, in routine surgical pathology there often is no attempt to classify amyloid other than staining to determine light chain–associated amyloidosis. Systemic and localized amyloidosis vary with respect to frequency of organ involvement by different amyloid types, and most amyloid proteins have commercial antibodies available for identification. Objective.— To provide a guide for the likelihood of amyloid type by organ system. Data Sources.— Literature review based on PubMed searches containing the word amyloid, specifically addressing the prevalence and significance of amyloid proteins in each organ system other than the brain, and the authors' practice experience. Conclusions.— In patients with amyloidosis, determination of the responsible protein is critical for appropriate patient care. In large subspecialty practices and reference laboratories with experience in using and analyzing relevant immunohistochemistry, most amyloid proteins can be identified with an organ-specific algorithm. Referring to an organ-based algorithm may be helpful in providing clinicians with a more specific differential diagnosis regarding amyloid type to help guide clinical evaluation and treatment. When the protein cannot be characterized, mass spectrometry can be performed to definitively classify the amyloid type.
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Miyazaki, S., A. Kadota, I. Mitsui, and T. Murakami. "Amyloid Signature Proteins in Feline Amyloidosis." Journal of Comparative Pathology 177 (May 2020): 10–17. http://dx.doi.org/10.1016/j.jcpa.2020.03.007.
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Kitamoto, Tetsuyuki, Kohtaro Hikita, Takatoshi Tashima, Jun Tateishi, and Yuji Sato. "Scrapie-associated fibrils (SAF) purification method yields amyloid proteins from systemic and cerebral amyloidosis." Bioscience Reports 6, no. 5 (May 1, 1986): 459–65. http://dx.doi.org/10.1007/bf01116137.
Повний текст джерелаАнотація:
We identified fibrils from non-transmissible systemic and cerebral amyloidosis using the purification method of scrapie-associated fibrils (SAF). The fibrils possessed the same nature of congophilia, filamentous structures and molecular weights as amyloid fibrils, and were resistant to Proteinase K digestion. This SAF method makes for a rapid extraction from amyloid-laden tissues. The method, therefore, may purify nontransmissible amyloids alone or together with SAF proteins.
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Goldis, Rivka, Batia Kaplan, Olga (Lesya) Kukuy, Michael Arad, Hila Magen, Efrat Shavit-Stein, Amir Dori, and Avi Livneh. "Diagnostic Challenges and Solutions in Systemic Amyloidosis." International Journal of Molecular Sciences 24, no. 5 (February 28, 2023): 4655. http://dx.doi.org/10.3390/ijms24054655.
Повний текст джерелаАнотація:
Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice.
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Pepys, M. B. "Pathogenesis, diagnosis and treatment of systemic amyloidosis." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1406 (February 28, 2001): 203–11. http://dx.doi.org/10.1098/rstb.2000.0766.
Повний текст джерелаАнотація:
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo , all such fibrils share a common cross–β core structure. Some natural wild–type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino–acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non–fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium–dependent binding to amyloid fibrils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non–invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end–stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo .
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Lin, Xuguang, Nuomin Galaqin, Reina Tainaka, Keiya Shimamori, Masahiro Kuragano, Taro Q. P. Noguchi, and Kiyotaka Tokuraku. "Real-Time 3D Imaging and Inhibition Analysis of Various Amyloid Aggregations Using Quantum Dots." International Journal of Molecular Sciences 21, no. 6 (March 13, 2020): 1978. http://dx.doi.org/10.3390/ijms21061978.
Повний текст джерелаАнотація:
Amyloidosis refers to aggregates of protein that accumulate and are deposited as amyloid fibrils into plaques. When these are detected in organs, they are the main hallmark of Alzheimer’s disease, Parkinson’s disease, and other related diseases. Recent medical advances have shown that many precursors and proteins can induce amyloidosis even though the mechanism of amyloid aggregation and the relationship of these proteins to amyloidosis remains mostly unclear. In this study, we report the real-time 3D-imaging and inhibition analysis of amyloid β (Aβ), tau, and α-synuclein aggregation utilizing the affinity between quantum dots (QD) and amyloid aggregates. We successfully visualized these amyloid aggregations in real-time using fluorescence microscopy and confocal microscopy simply by adding commercially available QD. The observation by transmission electron microscopy (TEM) showed that QD particles bound to all amyloid fibrils. The 3D-imaging with QD revealed differences between amyloid aggregates composed of different amyloid peptides that could not be detected by TEM. We were also able to quantify the inhibition activities of these proteins by rosmarinic acid, which has high activity for Aβ aggregation, from fluorescence micrographs as half-maximal effective concentrations. These imaging techniques with QD serve as quick, easy, and powerful tools to understand amyloidosis and to discover drugs for therapies.
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Turiak, Lilla, Bálint Kaszás, Krisztián Katona, Ágnes Lacza, László Márk, Károly Vékey, László Drahos, and Tamás Tornóczky. "Localized Amyloidosis of the Upper Aerodigestive Tract: Complex Analysis of the Cellular Infiltrate and the Amyloid Mass." Analytical Cellular Pathology 2019 (August 19, 2019): 1–9. http://dx.doi.org/10.1155/2019/6165140.
Повний текст джерелаАнотація:
Objectives. The aim of this study was to analyse the composition of amyloid mass and the plasmacytic infiltrate of localized amyloidosis of the upper aerodigestive tract. Methods. Biopsy materials were studied by light microscopy, immunohistochemistry (IHC), and mRNA in situ hybridization (mRNA-ISH). The amyloid mass was also analysed with high-performance liquid chromatography mass spectrometry- (HPLC-MS-) based proteomics. Results. Nodular and diffuse forms of amyloid deposition were detected. IHC analysis revealed λ-light chain (LC) in two cases, κ-LC in one case. The remaining two were positive with both. Proteins, well known from other amyloidoses like amyloid A (AA), prealbumin/transthyretin (PA), apolipoprotein A-I (ApoAI), and amyloid P component (APC), and also keratin were found with variable intensities in the cases. HPLC-MS revealed dozens of proteins with both LCs in all the lesions but sometimes with surprisingly small intensities. mRNA-ISH analysis revealed identical λ and κ dominance and only one normal κ/λ cell ratio. Conclusion. Cellular infiltrate and protein components in the amyloid showed congruent results in all but one case. The only exception with normal cell ratio and λ-dominant amyloid could be originated from the different protein-secreting activity of plasma cell clones. HPLC-MS analysis explored both LCs in all the amyloid in variable amount, but other proteins with much higher intensities like keratins, apolipoprotein A-IV (ApoAIV), were also detected. Proteins like AA, PA, ApoAI, and APC, previously known about amyloid-forming capability, also appeared. This indicates that localized amyloid in the upper aerodigestive tract is not a homogenous immunoglobulin mass but a mixture of proteins. The sometimes very low light chain intensities might also suggest that not all the localized amyloidosis cases of the upper aerodigestive tract are of convincingly AL type, and the analysis of the cellular infiltrate might indicate that not all are monoclonal.
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Westermark, Per, and Gunilla T. Westermark. "Reflections on amyloidosis in Papua New Guinea." Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1510 (November 27, 2008): 3701–5. http://dx.doi.org/10.1098/rstb.2008.0073.
Повний текст джерелаАнотація:
The amyloidoses comprise a heterogeneous group of diseases in which 1 out of more than 25 human proteins aggregates into characteristic beta-sheet fibrils with some unique properties. Aggregation is nucleation dependent. Among the known amyloid-forming constituents is the prion protein, well known for its ability to transmit misfolding and disease from one individual to another. There is increasing evidence that other amyloid forms also may be transmissible but only if certain prerequisites are fulfilled. One of these forms is systemic AA-amyloidosis in which an acute-phase reactant, serum AA, is over-expressed and, possibly after cleavage, aggregates into amyloid fibrils, causing disease. In a mouse model, this disorder can easily be transmitted from one animal to another both by intravenous and oral routes. Also, synthetic amyloid-like fibrils made from defined small peptides have this property, indicating a prion-like transmission mechanism. Even some fibrils occurring in the environment can transmit AA-amyloidosis in the murine model. AA-amyloidosis is particularly common in certain areas of Papua New Guinea, probably due to the endemicity of malaria and perhaps genetic predisposition. Now, when kuru is disappearing, more interest should be focused on the potentially lethal systemic AA-amyloidosis.
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Merlini, Giampaolo. "AL amyloidosis: from molecular mechanisms to targeted therapies." Hematology 2017, no. 1 (December 8, 2017): 1–12. http://dx.doi.org/10.1182/asheducation-2017.1.1.
Повний текст джерелаАнотація:
AbstractSystemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic amyloidosis, light-chain (AL) amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
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Picken, Maria M. "The Pathology of Amyloidosis in Classification: A Review." Acta Haematologica 143, no. 4 (2020): 322–34. http://dx.doi.org/10.1159/000506696.
Повний текст джерелаАнотація:
Background: The amyloidoses are a rare and heterogeneous group of disorders that are characterized by the deposition of abnormally folded proteins in tissues ultimately leading to organ damage. The deposits are mainly extracellular and are recognizable by their affinity for Congo red and their yellow-green birefringence under polarized light. Current classification of amyloid in medical practice is based on the amyloid protein type. To date, 36 proteins have been identified as being amyloidogenic in humans. Summary: in clinical practice, it is critical to distinguish between treatable versus non-treatable amyloidoses. Moreover, amyloidoses with a genetic component must be distinguished from the sporadic types and systemic amyloidoses must be distinguished from the localized forms. Among the systemic amyloidoses, AL continues to be the most common amyloid diagnosis in the developed world; other clinically significant types include AA, ALECT2, and ATTR. The latter is emerging as an underdiagnosed type in both the hereditary and wild-type setting. Other hereditary amyloidoses include AFib, several amyloidoses derived from apolipoproteins, AGel, ALys, etc. In a dialysis setting, systemic amyloid derived from β2 microglobulin (Aβ2M) should be considered, although a very rare hereditary variant has also been reported; several amyloidoses may be typically associated with aging and several iatrogenic types have also emerged. Determination of the amyloid protein type is imperative before specific therapy can be implemented and the current methods are briefly summarized. A brief overview of the target organ involvement by amyloid type is also included. Key Messages: (1) Early diagnosis of amyloidosis continues to pose a significant challenge and requires the participation of many clinical and laboratory specialties. (2) Determination of the protein type is imperative before specific therapy can be implemented. (3) While mass spectrometry has emerged as the preferred method of amyloid typing, careful application of immune methods is still clinically useful but caution and experience, as well as awareness of the limitations of each method, are necessary in their interpretation. (4) While the spectrum of amyloidoses continues to expand, it is critical to distinguish between those that are currently treatable versus those that are untreatable and avoid causing harm by inappropriate treatment.
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Yakupova, Elmira I., Liya G. Bobyleva, Sergey A. Shumeyko, Ivan M. Vikhlyantsev, and Alexander G. Bobylev. "Amyloids: The History of Toxicity and Functionality." Biology 10, no. 5 (May 1, 2021): 394. http://dx.doi.org/10.3390/biology10050394.
Повний текст джерелаАнотація:
Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans.
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Kourelis, Taxiarchis, Surendra Dasari, Ahmed U. Fayyaz, Martha Grogan, Marina Ramirez-Alvarado, Margaret Redfield, Omar F. abou Ezzeddine, Angela Dispenzieri, and Ellen D. McPhail. "A Proteomic Atlas of Cardiac Amyloidosis." Blood 134, Supplement_1 (November 13, 2019): 1790. http://dx.doi.org/10.1182/blood-2019-124802.
Повний текст джерелаАнотація:
The transthyretin (TTR) and immunoglobulin light chain proteins do not exist in isolation in cardiac amyloid (CA) plaques. Laser microdissection followed by mass spectrometry-based proteomic (LMD-MS) typing techniques can identify hundreds of co-deposited proteins in the "nano-environment" of amyloid deposits. Some, such as the "amyloid signature" proteins (SAP, APOE, APOA4, vitronectin, clusterin), are specific for amyloid plaques across different tissues and amyloid types. However, many of the remaining proteins are also abundant in the serum or normal tissues making it difficult to discern if they are unique to the amyloid plaque or part of the normal tissue background. We included 288 patients/samples with TTR CA (of which 53 were mutated) diagnosed by endomyocardial biopsy and 5 normal control samples obtained from 3 patients during autopsy. At the time of the meeting updated analyses including 168 cardiac light chain amyloid patients and 15 controls from patients with restrictive and hypertensive cardiomyopathy will be presented. Normalized spectral counts were used as a semi-quantitative measure of abundance. Proteins were considered part of the proteome if their abundance in the amyloid plaque was increased by 1.5-fold compared to normal controls (FDR p<0.05). Of 2240 unique proteins identified across all samples, 42 were differentially expressed in amyloid plaques. These included a) signature proteins: SAP, APOE, APOA4, vitronectin, clusterin; b) serum proteins: albumin, b2-glycoprotein, 7 complement pathway proteins; c) matrix proteins: 2 collagen isoforms, fibulin 1, decorin, PCOLCE2, TIMP3; d) cytosketal and contractile proteins: 2 actin isoforms, MYL2, 8 myosin isoforms, 3 ankyrin isofroms, desmin; and "other" proteins: serpine2, MAGE-like protein-2, pleiotrophin, AMBP, SRPX and QSOX1). The signature and cytoskeletal proteins were the most abundant overall, however, proteins that were most increased compared to normal included (log2 fold change in parentheses): fibulin (24.5), PCOLCE2 (23.5), b2-glycoprotein (23.5), factor H related peptide-2 (24.2), serpine2 (24.7), mage-like protein-2 (22.8), pleiotrophin (23.8), QSOX1 (22.9), SRPX (23.5). B2 glycoprotein was more abundant in wild type TTR samples(p=0.003). APOE (p=0.002), fibulin (p=0.008) and serpine2 (p<0.0001) were more abundant in UK stage (Gilmore JD et al, Eur Heart J 2018) 2/3 patients. Unsupervised hierarchical clustering of patients by normalized protein abundance revealed two major distinct patterns of co-deposited proteins (figure). Patients with high levels of contractility proteins (myosin isoforms, desmin, actins) were characterized by low levels of most other proteins (clusters on the left). Most complement proteins co-deposited along with higher levels of signature proteins (clusters on the right). When comparing clinical and laboratory characteristics between those 2 groups of patients only cardiac strain was found to be significantly higher (worse) in patients with lower levels of contractility proteins (p=0.01). Our data shows that the TTR CA proteome includes signature, serum and cardiac tissue proteins with variable expression according to TTR mutation status and cardiac functional status, which could inform mechanisms of disease pathogenesis. Comparison with diseased controls may further clarify if this proteomic pattern is specific to CA. Figure Disclosures Dasari: The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding.
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Loo, Dorothy, Peter N. Mollee, Patricia Renaut, and Michelle M. Hill. "Proteomics in Molecular Diagnosis: Typing of Amyloidosis." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/754109.
Повний текст джерелаАнотація:
Amyloidosis is a group of disorders caused by deposition of misfolded proteins as aggregates in the extracellular tissues of the body, leading to impairment of organ function. Correct identification of the causal amyloid protein is absolutely crucial for clinical management in order to avoid misdiagnosis and inappropriate, potentially harmful treatment, to assess prognosis and to offer genetic counselling if relevant. Current diagnostic methods, including antibody-based amyloid typing, have limited ability to detect the full range of amyloid forming proteins. Recent investigations into proteomic identification of amyloid protein have shown promise. This paper will review the current state of the art in proteomic analysis of amyloidosis, discuss the suitability of techniques based on the properties of amyloidosis, and further suggest potential areas of development. Establishment of mass spectrometry aided amyloid typing procedures in the pathology laboratory will allow accurate amyloidosis diagnosis in a timely manner and greatly facilitate clinical management of the disease.
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Ng, Christina Hui Lee, Gerald J. Berry, and Edward J. Damrose. "ATTR Variant Amyloidosis in Patients with Dysphagia." Surgeries 4, no. 2 (June 6, 2023): 275–82. http://dx.doi.org/10.3390/surgeries4020028.
Повний текст джерелаАнотація:
Amyloidosis is a rare disease characterized by the accumulation of misfolded extracellular proteins in various organs. Over 30 precursor proteins have been identified that can form amyloid deposits in different parts of the body. The most frequently encountered amyloidosis variant is the immunoglobulin light chain amyloid (AL). In this report, we present a unique case of a patient with biopsy-confirmed hypopharyngeal amyloidosis caused by transthyretin (ATTR). While hypopharyngeal involvement has been hypothesized in the past, conclusive reports are lacking, although rare instances of hypopharyngeal involvement by the AL variant of amyloidosis have been reported. We present the first case of biopsy-proven ATTR systemic amyloidosis with cardiomyopathy and hypopharyngeal involvement.
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Saito, Yukihiro, Kazufumi Nakamura, and Hiroshi Ito. "Molecular Mechanisms of Cardiac Amyloidosis." International Journal of Molecular Sciences 23, no. 1 (December 21, 2021): 25. http://dx.doi.org/10.3390/ijms23010025.
Повний текст джерелаАнотація:
Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis.
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Morgan, Gareth J. "Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis." Molecules 26, no. 12 (June 11, 2021): 3571. http://dx.doi.org/10.3390/molecules26123571.
Повний текст джерелаАнотація:
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
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Almeida, Zaida L., and Rui M. M. Brito. "Amyloid Disassembly: What Can We Learn from Chaperones?" Biomedicines 10, no. 12 (December 17, 2022): 3276. http://dx.doi.org/10.3390/biomedicines10123276.
Повний текст джерелаАнотація:
Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer’s, Parkinson’s, Huntington’s, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis.
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Sakata, Naohiro, Yoshinobu Hoshii, Tomomi Nakamura, Makiko Kiyama, Hirofumi Arai, Masatoshi Omoto, Mitsunori Morimatsu, and Tokuhiro Ishihara. "Colocalization of Apolipoprotein AI in Various Kinds of Systemic Amyloidosis." Journal of Histochemistry & Cytochemistry 53, no. 2 (February 2005): 237–42. http://dx.doi.org/10.1369/jhc.4a6387.2005.
Повний текст джерелаАнотація:
Apolipoprotein AI (apoAI), a major component of high-density lipoproteins, is one of the major amyloid fibril proteins and a minor constituent of the senile plaques observed in Alzheimer's disease. We examined colocalization of apoAI in various kinds of systemic amyloidosis in this study. Forty-three of 48 formalin-fixed paraffin-embedded heart specimens with various forms of systemic amyloidosis reacted immunohistochemically with anti-human apoAI antibody. ApoAI was also detected in water-extracted amyloid material by immunoblotting. In addition, we observed colocalization of apoAI and murine amyloid A (AA) amyloidosis in human apoAI transgenic mice. This is the first report of colocalization of apoAI with amyloid deposits in various forms of human systemic amyloidosis and murine AA amyloidosis in human apoAI transgenic mice. ApoAI may not always be a major component of amyloid fibrils, even when it is present in systemic amyloid deposits.
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Johnson, Kenneth H., Per Westermark, Knut Sletten, and Timothy D. O'brien. "Amyloid proteins and amyloidosis in domestic animals." Amyloid 3, no. 4 (January 1996): 270–89. http://dx.doi.org/10.3109/13506129609014375.
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Cunnane, Gaye. "Amyloid proteins in pathogenesis of AA amyloidosis." Lancet 358, no. 9275 (July 2001): 4–5. http://dx.doi.org/10.1016/s0140-6736(00)05297-1.
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Binder, Christina, and Franz Duca. "Diagnosis and supportive therapeutic management of cardiac light chain amyloidosis—a cardiologist’s perspective." memo - Magazine of European Medical Oncology 14, no. 1 (January 22, 2021): 89–97. http://dx.doi.org/10.1007/s12254-021-00678-5.
Повний текст джерелаАнотація:
SummaryCardiac amyloidosis is caused by deposition of abnormally folded proteins (amyloid). The most common forms of amyloidosis which present with cardiac involvement are light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Even with novel treatments emerging, the prognosis of these patients remains poor once amyloid deposits in the heart. Therefore, knowledge on clinical and imaging features of cardiac amyloidosis is crucial to make an early diagnosis and improve patient outcomes. This article reviews the most important diagnostic findings of cardiac amyloidosis and gives an overview on the therapeutic management of these patients, including supportive-, device- and disease-specific drug therapies focusing on AL amyloidosis.
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Leung, Nelson, Samih H. Nasr, and Sanjeev Sethi. "How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing." Blood 120, no. 16 (October 18, 2012): 3206–13. http://dx.doi.org/10.1182/blood-2012-03-413682.
Повний текст джерелаАнотація:
Abstract Amyloidosis is a rare group of diseases characterized by deposition of amyloid fibrils in soft tissues. More than 28 types of amyloid have been identified. They all share common ultrastructural and chemical characteristics. Treatments are available for many types but are type specific. Therefore, confirmation and typing of amyloid are essential before initiating treatment. Monoclonal protein studies should be performed on suspected cases, but the diagnosis requires a tissue biopsy. Congo red stain and electron microscopy are helpful to discriminate between amyloid and other pathologic fibrils. Once amyloid is confirmed, typing should be performed. Immunofluorescence and immunohistochemistry are frequently used and are helpful, but this approach has limitations, such as availability, specificity and sensitivity of commercial antibodies. Genetic mutational analysis is vital for ruling in and out hereditary amyloidoses but is unhelpful in nonmutated forms. The most advanced technique of amyloid typing is laser microdissection followed by mass spectrometry. Using proteomics, laser microdissection followed by mass spectrometry can directly identify proteins with or without mutations. Finally, imaging studies, such as cardiac MRI with gadolinium and 123I-labeled SAP scintigraphy not only assist in evaluation of patients with known amyloidosis but cardiac MRI has detected amyloid in patients previously unsuspected of the disease.
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Minnella, Angelo Maria, Roberta Rissotto, Elena Antoniazzi, Marco Di Girolamo, Marco Luigetti, Martina Maceroni, Daniela Bacherini, Benedetto Falsini, Stanislao Rizzo, and Laura Obici. "Ocular Involvement in Hereditary Amyloidosis." Genes 12, no. 7 (June 22, 2021): 955. http://dx.doi.org/10.3390/genes12070955.
Повний текст джерелаАнотація:
The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.
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Palstrøm, Nicolai Bjødstrup, Aleksandra M. Rojek, Hanne E. H. Møller, Charlotte Toftmann Hansen, Rune Matthiesen, Lars Melholt Rasmussen, Niels Abildgaard, and Hans Christian Beck. "Classification of Amyloidosis by Model-Assisted Mass Spectrometry-Based Proteomics." International Journal of Molecular Sciences 23, no. 1 (December 28, 2021): 319. http://dx.doi.org/10.3390/ijms23010319.
Повний текст джерелаАнотація:
Amyloidosis is a rare disease caused by the misfolding and extracellular aggregation of proteins as insoluble fibrillary deposits localized either in specific organs or systemically throughout the body. The organ targeted and the disease progression and outcome is highly dependent on the specific fibril-forming protein, and its accurate identification is essential to the choice of treatment. Mass spectrometry-based proteomics has become the method of choice for the identification of the amyloidogenic protein. Regrettably, this identification relies on manual and subjective interpretation of mass spectrometry data by an expert, which is undesirable and may bias diagnosis. To circumvent this, we developed a statistical model-assisted method for the unbiased identification of amyloid-containing biopsies and amyloidosis subtyping. Based on data from mass spectrometric analysis of amyloid-containing biopsies and corresponding controls. A Boruta method applied on a random forest classifier was applied to proteomics data obtained from the mass spectrometric analysis of 75 laser dissected Congo Red positive amyloid-containing biopsies and 78 Congo Red negative biopsies to identify novel “amyloid signature” proteins that included clusterin, fibulin-1, vitronectin complement component C9 and also three collagen proteins, as well as the well-known amyloid signature proteins apolipoprotein E, apolipoprotein A4, and serum amyloid P. A SVM learning algorithm were trained on the mass spectrometry data from the analysis of the 75 amyloid-containing biopsies and 78 amyloid-negative control biopsies. The trained algorithm performed superior in the discrimination of amyloid-containing biopsies from controls, with an accuracy of 1.0 when applied to a blinded mass spectrometry validation data set of 103 prospectively collected amyloid-containing biopsies. Moreover, our method successfully classified amyloidosis patients according to the subtype in 102 out of 103 blinded cases. Collectively, our model-assisted approach identified novel amyloid-associated proteins and demonstrated the use of mass spectrometry-based data in clinical diagnostics of disease by the unbiased and reliable model-assisted classification of amyloid deposits and of the specific amyloid subtype.
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Sharma, Vandna, and Kalyan Sundar Ghosh. "Inhibition of Amyloid Fibrillation by Small Molecules and Nanomaterials: Strategic Development of Pharmaceuticals Against Amyloidosis." Protein & Peptide Letters 26, no. 5 (May 29, 2019): 315–23. http://dx.doi.org/10.2174/0929866526666190307164944.
Повний текст джерелаАнотація:
Amyloid fibrils are a special class of self-assembled protein molecules, which exhibit various toxic effects in cells. Different physiological disorders such as Alzheimer’s, Parkinson’s, Huntington’s diseases, etc. happen due to amyloid formation and lack of proper cellular mechanism for the removal of fibrils. Therefore, inhibition of amyloid fibrillation will find immense applications to combat the diseases associated with amyloidosis. The development of therapeutics against amyloidosis is definitely challenging and numerous strategies have been followed to find out anti-amyloidogenic molecules. Inhibition of amyloid aggregation of proteins can be achieved either by stabilizing the native conformation or by decreasing the chances of assembly formation by the unfolded/misfolded structures. Various small molecules such as naturally occurring polyphenols, flavonoids, small organic molecules, surfactants, dyes, chaperones, etc. have demonstrated their capability to interrupt the amyloid fibrillation of proteins. In addition to that, in last few years, different nanomaterials were evolved as effective therapeutic inhibitors against amyloidosis. Aromatic and hydrophobic interactions between the partially unfolded protein molecules and the inhibitors had been pointed as a general mechanism for inhibition. In this review article, we are presenting an overview on the inhibition of amyloidosis by using different small molecules (both natural and synthetic origin) as well as nanomaterials for development of pharmaceutical strategies against amyloid diseases.
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Faust, Dominik, Bora Akoglu, Gordana Ristic, and Vladan Milovic. "Ursodeoxycholic acid for treatment of cholestasis in patients with hepatic amyloidosis." Vojnosanitetski pregled 66, no. 6 (2009): 482–86. http://dx.doi.org/10.2298/vsp0906482f.
Повний текст джерелаАнотація:
Background. Amyloidosis represents a group of different diseases characterized by extracellular accumulation of pathologic fibrillar proteins in various tissues and organs. Severe amyloid deposition in the liver parenchyma has extrahepatic involvement predominantly in the kidney or heart. We evaluated the effect of ursodeoxycholic acid, in four patients with severe hepatic amyloidosis of different etiologies, who presented with increased alkaline phosphatase and ?-glutamyl transferase. Case report. The study included four patients who presented with amyloidosis-associated intrahepatic cholestasis. Three of them had renal amyloidosis which developed 1-3 years before cholestasis occurred, the remaining one having intrahepatic cholestasis as the primary sign of the disease. Amyloidosis was identified from liver biopsies in all patients by its specific binding to Congo red and green birefringence in polarized light. The biochemical nature and the class of amyloid deposits were identified immunohistochemically. In addition to their regular treatment, the patients received 750 mg ursodeoxycholic acid per day. After 2-4 weeks all patients had a significant decrease of serum alkaline phosphatase and ?-glutamyl transferase, and their general status significantly improved. Conclusion. Treatment with ursodeoxycholic acid may be beneficial in patients with hepatic amyloidosis, and do extend indications for the use of ursodeoxycholic acid in amyloidotic cholestatic liver disease.
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Hyun, Ki Jong, Sung Hoon Kim, Lucia Kim, and Ji Won Kim. "Oral Phase Dysphagia, the First Manifestation of Systemic Amyloidosis Associated with Multiple Myeloma." Korean Journal of Otorhinolaryngology-Head and Neck Surgery 64, no. 8 (August 21, 2021): 576–79. http://dx.doi.org/10.3342/kjorl-hns.2020.00402.
Повний текст джерелаАнотація:
Amyloidosis is a disease in which abnormal proteins called amyloid accumulates in various tissues. In the head and neck area, the larynx is the most common site with the rare involvement of the tongue, causing symptoms of macroglossia. Most of amyloid light-chain (AL) amyloidosis are systemic amyloidosis accompanied with multiple myeloma (MM), where the involvement of tongue can be often observed. We report a case of AL amyloidosis with MM, initially with symptoms of dysarthria and dysphagia without macroglossia, but gradually over the years, macroglossia and high tongue stiffness were observed.
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Cowan, Andrew J., Martha Skinner, J. Mark Sloan, John L. Berk, Carl J. O'Hara, David C. Seldin, and Vaishali Sanchorawala. "Macroglossia – Not Always AL Amyloidosis." Blood 116, no. 21 (November 19, 2010): 5007. http://dx.doi.org/10.1182/blood.v116.21.5007.5007.
Повний текст джерелаАнотація:
Abstract Abstract 5007 Introduction: Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations: A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion: While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures: No relevant conflicts of interest to declare.
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Nakamura, Kazufumi. "Molecular Research on Amyloidosis." International Journal of Molecular Sciences 24, no. 8 (April 10, 2023): 6980. http://dx.doi.org/10.3390/ijms24086980.
Повний текст джерела
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Argiles, A., G. Mourad, C. Axelrud-Cavadore, A. Watrin, C. Mion, and J. C. Cavadore. "High-molecular-mass proteins in haemodialysis-associated amyloidosis." Clinical Science 76, no. 5 (May 1, 1989): 547–52. http://dx.doi.org/10.1042/cs0760547.
Повний текст джерелаАнотація:
1. Protein constituents were determined in eight amyloid deposits from eight patients (five male and three female), 53 ± 4 years of age, treated by haemodialysis for 9-20 years using only cuprophane membranes and operated for carpal tunnel syndrome. 2. Soluble proteins were removed by solubilization in phosphate-buffered saline after osmotic lysis. The proteins of the insoluble fibrils were characterized by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and two-dimensional gel electrophoresis, and immunologically identified by Western blotting. 3. In addition to β2-microglobulin, α2-macroglobulin was identified in the fibrillar material. The presence of these two proteins in amyloid deposits was confirmed by immunofluorescent microscopic studies. 4. Our data confirm the presence of β2-microglobulin in haemodialysis-associated amyloidosis, and also suggest a possible role for α2-microglobulin: it may protect β2-microglobulin from proteolytic digestion, leading to its accumulation in intact form and to amyloid fibril formation.
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Cowan, Andrew J., David G. Coffey, Teresa S. Hyun, Pamela S. Becker, Damian J. Green, Leona A. Holmberg, Ajay K. Gopal, and Edward N. Libby. "Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant." Blood 128, no. 22 (December 2, 2016): 5601. http://dx.doi.org/10.1182/blood.v128.22.5601.5601.
Повний текст джерелаАнотація:
Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.
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Li, Guoliang, Dan Han, Suhua Wei, Huaiyu Wang, and Limei Chen. "Multiorgan involvement by amyloid light chain amyloidosis." Journal of International Medical Research 47, no. 4 (February 25, 2019): 1778–86. http://dx.doi.org/10.1177/0300060518814337.
Повний текст джерелаАнотація:
Amyloid light chain (AL) amyloidosis is a protein conformational disease. AL amyloidosis results from aggregation of misfolded proteins that are deposited in tissues as amyloid fibrils. Diagnosis of AL amyloidosis can be challenging due to its low incidence and clinical complexity. Therapy requires a risk-adapted approach involving dose reductions and schedule modifications of chemotherapy regimens along with close monitoring of hematologic and organ responses. We herein describe a patient whose condition was diagnosed as systemic AL amyloidosis and presented with splenic rupture as the initial symptom. Congo red staining of the kidney biopsy was positive. The normal structure of the liver and spleen had been replaced by amyloid deposition. The chemotherapy strategy involved a combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone.
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Alkukhun, Abedalrazaq, Issa Rezek, Saber Ghiassi, Xuchen Zhang, and Margarita V. Revzin. "Mesenteric Amyloidosis: Radiologic Imaging with Pathologic Correlation." Journal of Clinical Imaging Science 10 (May 2, 2020): 24. http://dx.doi.org/10.25259/jcis_10_2020.
Повний текст джерелаАнотація:
Amyloidosis is a rare disease that is characterized by abnormal deposition of amyloid proteins in tissues, resulting in local, or systemic disease. When localized, it can present as an amyloidoma. We report a case of mesenteric amyloidosis in an 80-year-old male who was found to have an incidental mesenteric mass that was biopsy-proven to represent non-light chain amyloid tissue.
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Vrana, Julie A., Jeffrey D. Gamez, Jason D. Theis, Timothy B. Plummer, Robert H. Bergen, Steven R. Zeldenrust, Paul J. Kurtin, Karen L. Grogg, and Ahmet Dogan. "A Clinical Test for the Identification of Amyloid Proteins in Biopsy Specimens by a Novel Method Based on Laser Microdissection and Mass Spectrometry." Blood 110, no. 11 (November 16, 2007): 1480. http://dx.doi.org/10.1182/blood.v110.11.1480.1480.
Повний текст джерелаАнотація:
Abstract The management of systemic amyloidosis relies on the treatment of the underlying etiology and differs radically for different amyloid types. Therefore, given that at least 25 different proteins have been associated with amyloidosis, accurate identification of proteins deposited as amyloid fibrils is an important clinical problem. In this study, we describe a novel method that can characterize amyloid subtypes using laser microdissection (LMD) and mass spectrometry (MS) on routinely processed paraffin-embedded tissues. The study used 60 cases consisting of 16 transthyretin, 9 serum amyloid-associated protein, 20 immunoglobulin light chain lambda, 5 immunoglobulin light chain kappa, and 10 amyloid negative control samples. The biopsy specimens studied included heart, kidney, gastrointestinal tract, lung and decalcified bone marrow specimens. The amyloid type in all cases was previously characterized based on clinical findings, immunohistochemistry and, where indicated, by molecular testing for transthyretin mutations. Amyloid plaques were captured from an 10 micron paraffin section exhibiting positive Congo Red staining using LMD. Proteins were extracted, digested with trypsin and identified following MS/MS using the Mascot search algorithm analysis. MS correctly identified each of the 4 types of amyloidosis analyzed. Serum Amyloid P component and Apolipoprotein E were also identified as constituents of the amyloid deposition. The analysis was successful on all tissue types including decalcified bone marrow specimens and small biopsy specimens such as endomycardial biopsies and renal biopsies. The use of LMD from paraffin embedded biopsies and subsequent analysis by MS allows identification of the type of amyloid protein deposited with high specificity and sensitivity. This method promises to be a clinical test for accurate identification of amyloid proteins in routinely processed biopsy specimens and overcomes many of the specificity and sensitivity issues associated with current methods such as immunohistochemistry.
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Wall, Jonathan S., Angela D. Williams, James S. Foster, Tina Richey, Alan Stuckey, Sallie Macy, Craig Wooliver, et al. "Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy." Proceedings of the National Academy of Sciences 115, no. 46 (October 30, 2018): E10839—E10848. http://dx.doi.org/10.1073/pnas.1805515115.
Повний текст джерелаАнотація:
Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting “peptope” comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4–mediated dissolution of a human AL amyloid extract implanted in mice.