Materiały źródłowe

• #1 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #2 Amyloidosis: Pathogenesis, Types, and Diagnosis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-031-10131-1_7

  Amyloidoses are rare pathological disorders caused by the extracellular deposition of insoluble protein fibrils. Amyloidogenesis is characterized by misfolding of the protein precursors and progressive aggregation into a highly ordered fibrillar structure that causes organ damage. […] Amyloidosis may be hereditary, caused by genetic mutations of the precursor proteins, or acquired induced by various causes including paraproteinaemia, chronic inflammatory, or infectious conditions.

• #3 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #4 Amyloidosis – Wikipedia

  https://en.wikipedia.org/wiki/Amyloidosis

  Amyloidoses can be considered protein misfolding diseases. The vast majority of proteins that have been found to form amyloid deposits are secreted proteins, so the misfolding and formation of amyloid occurs outside cells, in the extracellular space. Of the 37 proteins so far identified as being vulnerable to amyloid formation, only four are cytosolic. Most amyloid-forming proteins are relatively small, but otherwise there is currently no evidence of structural or functional similarities among proteins known to form disease-associated amyloids. One third of amyloid disease is hereditary, in which case there is normally an early age of onset. Half of amyloid-related diseases are sporadic and have a late age of onset in these cases, the protein aggregation may be associated with aging-related decline in protein regulation. Some medical treatments are associated with amyloid disease, but this is rare.

• #5 AMYLOIDOSIS: PART 2: Pathogenesis & Classification – Pathology Made Simple

  https://ilovepathology.com/amyloidosis-part-2-pathogenesis-classification/

  The basic mechanism in the pathogenesis of amyloidosis is abnormal folding of proteins or misfolded proteins. Under normal circumstances, these abnormal or misfolded proteins are degraded by proteasome pathway intracellularly and by the macrophages extracellularly. In Amyloidosis, these control mechanisms fail or there may be mutations which favor misfolding which further leads to accumulation and aggregation to form fibrils. […] So, the pathogenesis can be broadly categorized into two mechanisms. […] Normal proteins, when produced in abnormal numbers. […] Production of normal amounts of mutant proteins. […] Direct cytotoxicity: eg, Amyloidogenic light chain accumulation in cardiac cells. […] Prefibrillar oligomers: are found to be more injurious than actual fibrils.

• #6 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  Proteins are prone to transitioning into an unstable unfolding state and require chaperones to maintain the correct folding structure. […] Misfolded proteins are usually degraded and removed by the proteasome, but some of them are released extracellularly and reassembled into a three-dimensional conformation that is rich in -sheets and polymerizable with each other to form amyloid fibrils. […] Amyloid fibril formation proceeds in two stages: nucleation and subsequent elongation. […] The nucleation phase refers to the process by which the misfolded protein monomers initially assemble to form a soluble oligomer, which forms the primary nucleus of amyloid fibrils. […] The tropism of organ involvement in amyloidosis depends on the type of amyloid precursor protein; however, the mechanism is not yet understood.

• #7 AMYLOIDOSIS: PART 2: Pathogenesis & Classification – Pathology Made Simple

  https://ilovepathology.com/amyloidosis-part-2-pathogenesis-classification/

  The basic mechanism in the pathogenesis of amyloidosis is abnormal folding of proteins or misfolded proteins. Under normal circumstances, these abnormal or misfolded proteins are degraded by proteasome pathway intracellularly and by the macrophages extracellularly. In Amyloidosis, these control mechanisms fail or there may be mutations which favor misfolding which further leads to accumulation and aggregation to form fibrils. […] So, the pathogenesis can be broadly categorized into two mechanisms. […] Normal proteins, when produced in abnormal numbers. […] Production of normal amounts of mutant proteins. […] Direct cytotoxicity: eg, Amyloidogenic light chain accumulation in cardiac cells. […] Prefibrillar oligomers: are found to be more injurious than actual fibrils.

• #8 Amyloidosis – Wikipedia

  https://en.wikipedia.org/wiki/Amyloidosis

  Amyloid-forming proteins aggregate into distinctive fibrillar forms with a beta-sheet structure. The beta-sheet form of amyloid is proteolysis-resistant, meaning it can not be degraded or broken down. As a result, amyloid deposits into the body’s extracellular space. The process of forming amyloid fibrils is thought to have intermediate oligomeric forms. Both the oligomers and amyloid fibrils can be toxic to cells and can interfere with proper organ function. The relative significance of different aggregation species may depend on the protein involved and the organ system affected.

• #9 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. […] Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. […] Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. […] The formation of amyloid fibrils, which is the essence of amyloidosis, requires multiple steps, such as the unfolding of precursor proteins, followed by misfolding, nucleation, polymerization, fiber elongation, and tissue deposition.

• #10 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  Proteins are prone to transitioning into an unstable unfolding state and require chaperones to maintain the correct folding structure. […] Misfolded proteins are usually degraded and removed by the proteasome, but some of them are released extracellularly and reassembled into a three-dimensional conformation that is rich in -sheets and polymerizable with each other to form amyloid fibrils. […] Amyloid fibril formation proceeds in two stages: nucleation and subsequent elongation. […] The nucleation phase refers to the process by which the misfolded protein monomers initially assemble to form a soluble oligomer, which forms the primary nucleus of amyloid fibrils. […] The tropism of organ involvement in amyloidosis depends on the type of amyloid precursor protein; however, the mechanism is not yet understood.

• #11 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  Proteins are prone to transitioning into an unstable unfolding state and require chaperones to maintain the correct folding structure. […] Misfolded proteins are usually degraded and removed by the proteasome, but some of them are released extracellularly and reassembled into a three-dimensional conformation that is rich in -sheets and polymerizable with each other to form amyloid fibrils. […] Amyloid fibril formation proceeds in two stages: nucleation and subsequent elongation. […] The nucleation phase refers to the process by which the misfolded protein monomers initially assemble to form a soluble oligomer, which forms the primary nucleus of amyloid fibrils. […] The tropism of organ involvement in amyloidosis depends on the type of amyloid precursor protein; however, the mechanism is not yet understood.

• #12 Dissection of the amyloid formation pathway in AL amyloidosis | Nature Communications

  https://www.nature.com/articles/s41467-021-26845-0

  In antibody light chain (AL) amyloidosis, overproduced light chain (LC) fragments accumulate as fibrils in organs and tissues of patients. […] The hallmark of AL amyloidosis is the transformation of soluble monomeric protein into insoluble amyloid fibrils. […] During restructuring, the internal disulfide bond is retained and hydrophobic core residues become surface-exposed. […] Like in other amyloid diseases, the growth phase of AL fibrils is preceded by a comparably long and rate-limiting lag phase in vitro. […] Understanding the pathway and molecular mechanism of reactions preceding fibril formation of pathogenic LCs is important to identify potential therapeutic intervention points at early stages of the disease. […] We show that, starting from the monomeric patient LC truncation Pat-16, small amounts of dimers are formed in the first hour of the lag phase.

• #13 AA (Inflammatory) Amyloidosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/335559-overview

  Several lines of evidence have indicated that the conversion of SAA into amyloid fibrils occurs through its specific interaction with heparan sulfate (HS), a ubiquitously expressed glycosaminoglycan component of the extracellular matrix. […] Chronic or acute, recurrent, substantial elevations of SAA are necessary but not sufficient for the development of amyloidosis. […] The factors responsible for determining the site of deposition in any form of amyloidosis have not been identified. […] The progression of amyloidosis is related to the production and concentration of the circulating amyloidogenic precursor protein. […] Sustained increased concentration of SAA is the most significant risk factor in AA amyloidosis, whereas reduction of SAA concentration improves survival and is associated with arrest or even regression of amyloid deposits.

• #14 AA (Inflammatory) Amyloidosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/335559-overview

  Several lines of evidence have indicated that the conversion of SAA into amyloid fibrils occurs through its specific interaction with heparan sulfate (HS), a ubiquitously expressed glycosaminoglycan component of the extracellular matrix. […] Chronic or acute, recurrent, substantial elevations of SAA are necessary but not sufficient for the development of amyloidosis. […] The factors responsible for determining the site of deposition in any form of amyloidosis have not been identified. […] The progression of amyloidosis is related to the production and concentration of the circulating amyloidogenic precursor protein. […] Sustained increased concentration of SAA is the most significant risk factor in AA amyloidosis, whereas reduction of SAA concentration improves survival and is associated with arrest or even regression of amyloid deposits.

• #15 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. […] Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. […] Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. […] The formation of amyloid fibrils, which is the essence of amyloidosis, requires multiple steps, such as the unfolding of precursor proteins, followed by misfolding, nucleation, polymerization, fiber elongation, and tissue deposition.

• #16 Amyloidosis – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/amyloidosis/amyloidosis

  Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. […] Amyloid fibrils are made of normally soluble misfolded proteins that aggregate into oligomers and then insoluble fibrils. […] For amyloidosis to develop, in addition to production of amyloidogenic proteins, there is probably also a failure of the normal clearance mechanisms for such misfolded proteins. The amyloid deposits themselves are metabolically inert but interfere physically with organ structure and function. However, some prefibrillar oligomers of amyloidogenic proteins have direct cellular toxicity, an important component of disease pathogenesis. […] The amyloidogenic protein determines the amyloid type and clinical course of disease, although the clinical manifestations of the different types may overlap.

• #17 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. […] Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. […] Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. […] The formation of amyloid fibrils, which is the essence of amyloidosis, requires multiple steps, such as the unfolding of precursor proteins, followed by misfolding, nucleation, polymerization, fiber elongation, and tissue deposition.

• #18 Amyloidosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178

  Amyloidosis (am-uh-loi-DO-sis) is a rare disease that occurs when a protein called amyloid builds up in organs. This amyloid buildup can make the organs not work properly. […] Some types of amyloidosis occur with other diseases. These types may improve with treatment of the other diseases. Some types of amyloidosis may lead to life-threatening organ failure. […] There are many different types of amyloidosis. Some types are hereditary. Others are caused by outside factors, such as inflammatory diseases or long-term dialysis. Many types affect multiple organs. Others affect only one part of the body. […] AL amyloidosis (immunoglobulin light chain amyloidosis). This is the most common type of amyloidosis in developed countries. AL amyloidosis is also called primary amyloidosis. It usually affects the heart, kidneys, liver and nerves.

• #19 AA amyloidosis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/aa-amyloidosis-pathogenesis

  AA amyloidosis: Pathogenesis […] The pathogenesis of AA amyloidosis is presented here. […] The process of amyloid formation and deposition causes tissue toxicity and progressive organ dysfunction. […] AA amyloid results from the deposition in tissue of serum amyloid A (SAA) protein, which is a major acute phase reactant. […] Amyloidosis encompasses a group of diseases caused by misfolding and extracellular accumulation of proteins as fibrillar deposits. […] The genetic factors potentially related to pathogenesis, clinical manifestations, diagnosis, and treatment of this disorder are discussed separately.

• #20 Amyloidosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178

  AA amyloidosis. This type is also known as secondary amyloidosis. It’s usually triggered by an inflammatory disease, such as rheumatoid arthritis. It most commonly affects the kidneys, liver and spleen. […] Hereditary amyloidosis (familial amyloidosis). This inherited disorder often affects the nerves, heart and kidneys. It most commonly happens when a protein made by your liver is abnormal. This protein is called transthyretin (TTR). […] Wild-type amyloidosis. This variety has also been called senile systemic amyloidosis. It occurs when the TTR protein made by the liver is normal but produces amyloid for unknown reasons. Wild-type amyloidosis tends to affect men over age 70 and often targets the heart. It can also cause carpal tunnel syndrome. […] Amyloid reduces the heart’s ability to fill with blood between heartbeats. Less blood is pumped with each beat. This can cause shortness of breath. If amyloidosis affects the heart’s electrical system, it can cause heart rhythm problems. Amyloid-related heart problems can become life-threatening.

• #21 Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/86/9/1036

  Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. […] Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. […] Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan.

• #22 Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment | IntechOpen

  https://www.intechopen.com/chapters/45266

  Amyloidosis is defined as an insoluble protein fibril that is deposited, mainly, in the extracellular spaces of organs and tissues as a result of a sequence of changes in protein folding. Precursor proteins change their conformation that forms amyloid fibrils, then deposited amyloid induce organ damage with disease specific conditions. […] In the nomenclature, dialysis-related amyloidosis (DRA) is defined as 2-microglobulin-related (A2M) amyloid which precursor protein is 2-microglobulin (2-m). It is associated to dialysis, a kidney replacement therapy, and deposits in systemic (S), mainly joint tissues. […] Long-term dialysis treatment for end-stage kidney disease often induces the A2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as carpal tunnel syndrome (CTS), destructive spondyloarthropathy (DSA), and cystic bone lesions as well as in systemic organs such as heart and gastrointestinal tract when disease advances. Several biomolecules including 2-m as well as clinical risk factors are thought to relate with A2M amyloidogenesis.

• #23 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #24 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #25 Frontiers | Association of Skin with the Pathogenesis and Treatment of Neurodegenerative Amyloidosis

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2012.00005/full

  In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. […] Recent research suggests that prefibrillar aggregates, soluble oligomers, rather than fibrils per se are the most potent mediators of cytotoxicity. […] However, the mechanism of amyloid formation and toxicity is still unknown; thus, there is not an effective treatment for any of the conformational diseases. […] Given that a common pathogenic mechanism may underlie in all of these diseases, treatments that target protein conformation could be applicable in a variety of contexts. […] At the molecular level several models have been postulated to explain the common mechanism of amyloidogenesis in protein misfolding disease. […] Amyloid species can transmit conformational changes in homologous and heterologous proteins, mechanisms denominated as seeding and cross-seeding, respectively.

• #26 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #27 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #28 Amyloid – Wikipedia

  https://en.wikipedia.org/wiki/Amyloid

  The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. […] The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves. […] Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. […] All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree.

• #29 Amyloid – Wikipedia

  https://en.wikipedia.org/wiki/Amyloid

  The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. […] The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves. […] Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. […] All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree.

• #30 Amyloid – Wikipedia

  https://en.wikipedia.org/wiki/Amyloid

  The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. […] The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves. […] Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. […] All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree.

• #31 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #32 Amyloidosis – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/amyloidosis/amyloidosis

  Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. […] Amyloid fibrils are made of normally soluble misfolded proteins that aggregate into oligomers and then insoluble fibrils. […] For amyloidosis to develop, in addition to production of amyloidogenic proteins, there is probably also a failure of the normal clearance mechanisms for such misfolded proteins. The amyloid deposits themselves are metabolically inert but interfere physically with organ structure and function. However, some prefibrillar oligomers of amyloidogenic proteins have direct cellular toxicity, an important component of disease pathogenesis. […] The amyloidogenic protein determines the amyloid type and clinical course of disease, although the clinical manifestations of the different types may overlap.

• #33 Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment | IntechOpen

  https://www.intechopen.com/chapters/45266

  Deposited amyloidosis induces compression that induced CTS and joint arthropathy. […] The progress through synovial inflammation and subsequent osteoclastogenesis and/or osteoclast activation through three possible pathways: (i) indirect action of inflammatory cytokines through the expression in osteoblasts of receptor activator of nuclear factor-B ligand/osteoprotegerin ligand (RANKL/OPGL), (ii) direct action of inflammatory cytokines, and (iii) RANKL/OPGL expression in inflammatory cells. […] Serum level of 2-m, precursor protein of DRA, increase in dialysis patients and is believed most important for onset and progress of DRA. […] DRA may be onset after accumulation of 2-m with long duration of dialysis treatment. […] Long-term dialysis treatment for end-stage kidney disease often induces the A2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as CTS, DSA, and cystic bone lesions as well as in rarely systemic organs such as heart and gastrointestinal tract when disease is advanced.

• #34 Amyloidosis: Causes, Types, Symptoms, Diagnosis, Treatment, and Prognosis

  https://www.webmd.com/cancer/lymphoma/amyloidosis-symptoms-causes-treatments

  Specific treatment depends on what type of amyloidosis you have and how many organs are affected. […] New therapies can slow the production of the abnormal protein TTR. […] Amyloid deposits in your heart can make the muscular walls of your heart stiff. They can also make your heart muscle weaker and affect the electrical rhythm of the heart, potentially causing serious risks to your health. […] Amyloid deposits in the kidneys make it hard for them to do this job. When your kidneys do not work properly, water and dangerous toxins build up in your body. […] Amyloid deposits along your gastrointestinal (GI) tract slow down the movement of food through your intestines. This interferes with digestion. […] Amyloid deposits can damage the nerves outside your brain and spinal cord, called the peripheral nerves. […] Researchers continue to question why some types of amyloid make people sick and how the formation of amyloid can be stopped. Studies to find new treatments are ongoing.

• #35 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  Proteins are prone to transitioning into an unstable unfolding state and require chaperones to maintain the correct folding structure. […] Misfolded proteins are usually degraded and removed by the proteasome, but some of them are released extracellularly and reassembled into a three-dimensional conformation that is rich in -sheets and polymerizable with each other to form amyloid fibrils. […] Amyloid fibril formation proceeds in two stages: nucleation and subsequent elongation. […] The nucleation phase refers to the process by which the misfolded protein monomers initially assemble to form a soluble oligomer, which forms the primary nucleus of amyloid fibrils. […] The tropism of organ involvement in amyloidosis depends on the type of amyloid precursor protein; however, the mechanism is not yet understood.

• #36 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #37 Amyloidosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178

  Amyloidosis (am-uh-loi-DO-sis) is a rare disease that occurs when a protein called amyloid builds up in organs. This amyloid buildup can make the organs not work properly. […] Some types of amyloidosis occur with other diseases. These types may improve with treatment of the other diseases. Some types of amyloidosis may lead to life-threatening organ failure. […] There are many different types of amyloidosis. Some types are hereditary. Others are caused by outside factors, such as inflammatory diseases or long-term dialysis. Many types affect multiple organs. Others affect only one part of the body. […] AL amyloidosis (immunoglobulin light chain amyloidosis). This is the most common type of amyloidosis in developed countries. AL amyloidosis is also called primary amyloidosis. It usually affects the heart, kidneys, liver and nerves.

• #38 Review of Pathogenesis, Research and Treatment of Amyloidosis Published in New England Journal of Medicine | Chobanian & Avedisian School of Medicine

  https://www.bumc.bu.edu/camed/2024/06/27/review-of-pathogenesis-research-and-treatment-of-amyloidosis-published-in-new-england-journal-of-medicine/

  AL (immunoglobulin light chain) amyloidosis is a rare disease that often results in progressive organ dysfunction, organ failure and eventual death. […] Clonal plasma cells in the bone marrow secrete free light chains into circulation. These light chains are part of immunoglobulins, also called antibodies. But in this disease, light chains misfold and aggregate into amyloid fibrils that deposit in organs and tissues. […] Sanchorawala focused on recent advances in the understanding of pathogenesis, clinical syndromes, risk stratification and therapeutic advances, and looking at future efforts and needs in treatment and research. […] One of the most important determinants of survival is the severity of cardiac involvement, said Sanchorawala. […] Therapies include those targeting clonal plasma cells, stopping light chain production, and new research into antifibril monoclonal antibodies that accelerate the removal of amyloid deposits from the organs. […] Despite improvements in the diagnosis and treatment of AL amyloidosis, continued basic and clinical research efforts are needed to brighten the future for patients with this disorder, said Sanchorawala.

• #39 AA (Inflammatory) Amyloidosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/335559-overview

  Amyloidosis comprises a heterogeneous group of diseases in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal, insoluble, fibrillar form. […] AA amyloidosis occurs in the course of chronic inflammatory diseases (infectious and noninfectious), hereditary periodic fevers, and with certain neoplasms, such as Hodgkin lymphoma and renal cell carcinoma. […] The tissue fibril involved in AA amyloidosis consists of a 7500-dalton cleavage product of the SAA protein. […] SAA protein is an acute phase reactant, like C-reactive protein (CRP), and is synthesized by hepatocytes under the transcriptional regulation of cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF). […] Elevated plasma concentrations of SAA lead to accumulations of amyloid in the form of cross—sheet fibrillar deposits. The mechanism of these cross—sheet fibrillar deposits is not completely understood at this time.

• #40 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  Advances in the understanding of the molecular mechanisms involved in amyloid formation and tissue damage have revealed several new drug targets and therapeutic approaches. […] Ultimately, amyloid diseases will be treated with combination cytotoxic, targeted, and immunologic approaches that reduce protein precursor production, prevent aggregation, and induce fibril resorption.

• #41 Review of Pathogenesis, Research and Treatment of Amyloidosis Published in New England Journal of Medicine | Chobanian & Avedisian School of Medicine

  https://www.bumc.bu.edu/camed/2024/06/27/review-of-pathogenesis-research-and-treatment-of-amyloidosis-published-in-new-england-journal-of-medicine/

  AL (immunoglobulin light chain) amyloidosis is a rare disease that often results in progressive organ dysfunction, organ failure and eventual death. […] Clonal plasma cells in the bone marrow secrete free light chains into circulation. These light chains are part of immunoglobulins, also called antibodies. But in this disease, light chains misfold and aggregate into amyloid fibrils that deposit in organs and tissues. […] Sanchorawala focused on recent advances in the understanding of pathogenesis, clinical syndromes, risk stratification and therapeutic advances, and looking at future efforts and needs in treatment and research. […] One of the most important determinants of survival is the severity of cardiac involvement, said Sanchorawala. […] Therapies include those targeting clonal plasma cells, stopping light chain production, and new research into antifibril monoclonal antibodies that accelerate the removal of amyloid deposits from the organs. […] Despite improvements in the diagnosis and treatment of AL amyloidosis, continued basic and clinical research efforts are needed to brighten the future for patients with this disorder, said Sanchorawala.

• #42 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #43 Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/86/9/1036

  Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.

• #44 Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/86/9/1036

  Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. […] Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. […] Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan.

• #45 Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/86/9/1036

  Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. […] Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. […] Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan.

• #46 Amyloidosis – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/amyloidosis/amyloidosis

  For hereditary ATTRv amyloidosis, small molecule stabilizer therapeutics and gene-silencing medications inhibit or potentially reverse neurologic deterioration; for patients with amyloid cardiomyopathy (ATTRv or ATTRwt), small molecule stabilizer medications have been shown to decrease all-cause mortality and cardiovascular-related hospitalizations.

• #47 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #48 Review of pathogenesis, research and treatment of amyloidosis published in New England Journal of Medicine | EurekAlert!

  https://www.eurekalert.org/news-releases/1049403

  AL (immunoglobulin light chain) amyloidosis is a rare disease that often results in progressive organ dysfunction, organ failure and eventual death. […] Clonal plasma cells in the bone marrow secrete free light chains into circulation. These light chains are part of immunoglobulins, also called antibodies. But in this disease, light chains misfold and aggregate into amyloid fibrils that deposit in organs and tissues. […] One of the most important determinants of survival is the severity of cardiac involvement, said Sanchorawala. The heart is affected in 70 to 80% of patients with AL amyloidosis and cardiac problems are the leading cause of death, but other major organs like kidneys, liver, and peripheral and autonomic nervous systems can also be affected by this disease. […] Therapies include those targeting clonal plasma cells, stopping light chain production, and new research into antifibril monoclonal antibodies that accelerate the removal of amyloid deposits from the organs. […] Despite improvements in the diagnosis and treatment of AL amyloidosis, continued basic and clinical research efforts are needed to brighten the future for patients with this disorder, said Sanchorawala.

• #49 A novel mechanism of action to address unmet needs in AL amyloidosis | Prothena

  https://www.prothena.com/a-novel-mechanism-of-action-to-address-unmet-needs-in-al-amyloidosis/

  AL amyloidosis, a rare, progressive and often fatal disease, occurs when a type of immune cell, called plasma cells, produce high levels of an abnormal protein called light chain that misfolds and clumps together to form aggregated amyloid which the body cannot break down. […] Current treatment strategies target plasma cells to reduce production of new abnormal light chains, but do not address the amyloid already deposited in vital organs. […] Birtamimab*, a potential first-in-class anti-amyloid treatment for AL amyloidosis, is an investigational humanized monoclonal antibody designed to specifically target and clear the amyloid that accumulates and causes organ dysfunction and failure in patients with AL amyloidosis. […] Last month, Prothena announced the publication of the mechanism of action, pharmacological characteristics and clinical utility of birtamimab in Leukemia Lymphoma, an international peer-reviewed journal that publishes research on all aspects of hematological malignancies.

• #50 AL Amyloidosis

  https://www.prothena.com/pipeline/al-amyloidosis/

  AL amyloidosis is a rare, progressive and typically fatal disease where clonal plasma cells produce light chain proteins that misfold, aggregate and deposit as amyloid in vital organs such as the heart. […] Current treatment strategies target plasma cells to reduce production of new light chain proteins, but do not address the toxic light chains and amyloid already deposited in vital organs. Mortality is driven primarily by cardiac failure. […] Birtamimab, formerly known as NEOD001, is an investigational monoclonal antibody designed to specifically and selectively target and clear toxic light chains and the amyloid that accumulates and causes organ dysfunction and failure in patients with AL amyloidosis. […] In preclinical studies, birtamimab has been shown to broadly react with a cryptic epitope that is exposed only on misfolded toxic kappa and lambda light chains. Birtamimab has a potential best-in-class anti-amyloid mechanism designed to neutralize toxic soluble aggregates and remove insoluble amyloid deposits in patients with AL amyloidosis with cardiac involvement.

• #51 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #52

  https://grantome.com/grant/NIH/I01-CX001631-03

  AA (secondary, reactive) amyloidosis is a disease caused by extracellular deposition of insoluble ?-pleated sheet fibrils composed of amyloid A (AA) protein, an N-terminal fragment of the acute phase protein serum amyloid A (SAA). The deposits disrupt tissue structure and eventually compromise organ function. […] AA amyloidosis usually develops as a complication of chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and the hereditary auto-inflammatory syndromes (e.g., familial Mediterranean fever). […] At present, there is no specific therapy for AA amyloidosis. Only control of pro-inflammatory stimuli to reduce hepatic SAA synthesis has shown an effect on AA amyloid progression. […] In a second aim we will explore the role of post-translational modification of SAA in the genesis of amyloid fibril formation. Our in vitro studies show that carbamylation of residues in the amino-terminal portion of mouse SAA1.1 has a potentiating effect on amyloid formation. This region of SAA is most crucial to the initiation and propagation of amyloid fibrils, suggesting that modifications in this region may have important consequences in vivo as well as in vitro. […] If modifications are found to impact amyloid formation in vivo as they do in vitro, targeting such modifications may offer new therapeutic options to treat this progressive, fatal disease.

• #53 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  Advances in the understanding of the molecular mechanisms involved in amyloid formation and tissue damage have revealed several new drug targets and therapeutic approaches. […] Ultimately, amyloid diseases will be treated with combination cytotoxic, targeted, and immunologic approaches that reduce protein precursor production, prevent aggregation, and induce fibril resorption.

• #54 Frontiers | Association of Skin with the Pathogenesis and Treatment of Neurodegenerative Amyloidosis

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2012.00005/full

  In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. […] Recent research suggests that prefibrillar aggregates, soluble oligomers, rather than fibrils per se are the most potent mediators of cytotoxicity. […] However, the mechanism of amyloid formation and toxicity is still unknown; thus, there is not an effective treatment for any of the conformational diseases. […] Given that a common pathogenic mechanism may underlie in all of these diseases, treatments that target protein conformation could be applicable in a variety of contexts. […] At the molecular level several models have been postulated to explain the common mechanism of amyloidogenesis in protein misfolding disease. […] Amyloid species can transmit conformational changes in homologous and heterologous proteins, mechanisms denominated as seeding and cross-seeding, respectively.

• #55 Pathogenesis, diagnostics and treatment of transthyretin amyloidosis

  https://www.umu.se/en/research/projects/pathogenesis-diagnostics-and-treatment-of-transthyretin-amyloidosis/

  Transthyretin amyloidosis (ATTR amyloidosis) is a lethal systemic disorder caused by deposition of protein fibrils (amyloid) in various organs. The amyloid is formed by misfolded transthyretin (TTR), which is mainly produced by the liver. […] Our group (Amyloidosis Center) is responsible for the treatment of ATTR amyloidosis in Sweden and conducts preclinical and clinical research on the pathogenesis, diagnostics and treatment of the disease since the 1980’s. Throughout the years, we have explored the prevalence, penetrance and clinical picture of ATTR amyloidosis in Sweden and studied the pathogenesis of the disease, especially with respect to its gastrointestinal complications. […] Our current research focuses on the study of different genetic factors (apart from TTR mutations) with possible impact on disease phenotype, potential biomarkers of disease, the impact of amyloid fibril type on disease outcome, and the accuracy of our current diagnostic methods.

• #56 Molecular Imaging of Cardiac Amyloidosis | Journal of Nuclear Medicine

  https://jnm.snmjournals.org/content/61/7/965

  The fibril type in V30M determines the clinical phenotype. […] Thus, calcification alone cannot fully explain the affinity of bone-seeking tracers to ATTR, and direct binding to fibrils cannot be excluded at this time. […] With the advent of effective treatment options for ATTR amyloidosis, a critical need has emerged for an imaging test to monitor disease activity by serial imaging.

• #57 Amyloidosis: Pathogenesis and New Therapeutic Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3138545/

  The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. […] The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are incompletely understood. […] A growing body of literature has implicated prefibrillar oligomers, rather than the fibrillar form, as the primary pathologic species of Alzheimer’s disease and ATTR amyloidosis. […] Direct cytotoxicity of amyloidogenic Ig light chains to cardiac cells has also been demonstrated. […] Thus, organ damage may occur through two intermingled mechanisms. […] These findings indicate that in AL amyloidosis, the amyloid precursor (the free light chain) plays an important role in tissue dysfunction and that it is essential to eliminate its production in the shortest possible time.

• #58 Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9181426/

  In AL, as will be described later, the gene polymorphism/amino acid sequence of the variable region of LC affects the tissue deposition pattern of amyloid fibrils. […] Organ damage in amyloidosis is generally thought to be caused by the mass effects of amyloid fibril deposition. […] However, especially in AL, the cytotoxicity exerted by LC oligomers and aggregates before amyloid fibril formation is also an important mechanism that causes tissue damage. […] To date, most studies elucidating the pathophysiology of AL have been conducted using human specimens, including their genomic analysis, elucidation of the features of neoplastic plasma cells in bone marrow, identification of amino acid sequences of amyloidogenic LCs, and structural analysis of amyloid fibrils. […] There are still many unclear points regarding the molecular mechanism of myocardial injury in AL, and progress in fundamental research is an urgent issue in this field.

• #59 Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/86/9/1036

  Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.

• #60 A novel mechanism of action to address unmet needs in AL amyloidosis | Prothena

  https://www.prothena.com/a-novel-mechanism-of-action-to-address-unmet-needs-in-al-amyloidosis/

  AL amyloidosis, a rare, progressive and often fatal disease, occurs when a type of immune cell, called plasma cells, produce high levels of an abnormal protein called light chain that misfolds and clumps together to form aggregated amyloid which the body cannot break down. […] Current treatment strategies target plasma cells to reduce production of new abnormal light chains, but do not address the amyloid already deposited in vital organs. […] Birtamimab*, a potential first-in-class anti-amyloid treatment for AL amyloidosis, is an investigational humanized monoclonal antibody designed to specifically target and clear the amyloid that accumulates and causes organ dysfunction and failure in patients with AL amyloidosis. […] Last month, Prothena announced the publication of the mechanism of action, pharmacological characteristics and clinical utility of birtamimab in Leukemia Lymphoma, an international peer-reviewed journal that publishes research on all aspects of hematological malignancies.

• #61 Review of Pathogenesis, Research and Treatment of Amyloidosis Published in New England Journal of Medicine | Chobanian & Avedisian School of Medicine

  https://www.bumc.bu.edu/camed/2024/06/27/review-of-pathogenesis-research-and-treatment-of-amyloidosis-published-in-new-england-journal-of-medicine/

  AL (immunoglobulin light chain) amyloidosis is a rare disease that often results in progressive organ dysfunction, organ failure and eventual death. […] Clonal plasma cells in the bone marrow secrete free light chains into circulation. These light chains are part of immunoglobulins, also called antibodies. But in this disease, light chains misfold and aggregate into amyloid fibrils that deposit in organs and tissues. […] Sanchorawala focused on recent advances in the understanding of pathogenesis, clinical syndromes, risk stratification and therapeutic advances, and looking at future efforts and needs in treatment and research. […] One of the most important determinants of survival is the severity of cardiac involvement, said Sanchorawala. […] Therapies include those targeting clonal plasma cells, stopping light chain production, and new research into antifibril monoclonal antibodies that accelerate the removal of amyloid deposits from the organs. […] Despite improvements in the diagnosis and treatment of AL amyloidosis, continued basic and clinical research efforts are needed to brighten the future for patients with this disorder, said Sanchorawala.

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