• FFPE storage
• H90D
• TTR
• proteomics
• variant misidentification

• Prealbumin/genetics
• Prealbumin/metabolism
• Prealbumin/chemistry
• Humans
• Animals
• Oxidation-Reduction
• Mice
• Amyloid/metabolism
• Amyloid/genetics
• Amyloid/chemistry
• Formaldehyde/chemistry
• Amyloid Neuropathies, Familial/genetics
• Amyloid Neuropathies, Familial/metabolism
• Amyloid Neuropathies, Familial/pathology
• Histidine/genetics
• Histidine/chemistry
• Histidine/metabolism
• Proteomics
• Male
• Female

• PG/16/76/32394 British Heart Foundation

• AA amyloid
• AL-kappa amyloid
• AL-lambda amyloid
• ATTR amyloid
• Subcutaneous abdominal fat aspirate
• amyloid quantification
• amyloid typing

• Humans
• Enzyme-Linked Immunosorbent Assay
• Male
• Female
• Middle Aged
• Aged
• Subcutaneous Fat, Abdominal/metabolism
• Subcutaneous Fat, Abdominal/pathology
• Amyloidosis/diagnosis
• Amyloidosis/metabolism
• Amyloidosis/pathology
• Amyloidosis/classification
• Amyloid/metabolism
• Adult
• Sensitivity and Specificity
• Aged, 80 and over

Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR^S52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α₂-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.

ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.

Apolipoprotein A‐IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA‐IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA‐IV signal sequence residues (p.18‐43 to p.20‐43) in 16/24 trypsin‐digested amyloid deposits but in only 1/266 non‐ApoA‐IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA‐IV amyloid was first described, and in plasma from a single cardiac ApoA‐IV amyloidosis patient. The most common signal‐containing peptide observed in ApoA‐IV amyloid, p.20‐43, and to a far lesser extent the N‐terminal peptide, p.21‐43, were fibrillogenic in vitro at physiological pH, generating Congo red‐positive fibrils. The addition of a single signal‐derived alanine residue to the N‐terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA‐IV‐associated pathologies. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

• ApoA-IV amyloidosis
• ApoA-IV sequence coverage
• ApoA-IV signal-containing peptide
• amyloid proteomics
• fibrillogenic ApoA-IV signal-containing peptide
• targeted mass spectrometry in serum

• Amyloid
• laser microdissection
• mass spectrometry
• proteome

• Changes of gastric mucosa
• Clinical presentations
• Gastroscopy
• Primary localized gastric amyloidosis
• Prognosis

• Aged
• Amyloidosis/diagnosis
• Amyloidosis/therapy
• Female
• Humans
• Prognosis
• Stomach

• acute allograft rejection
• extracellular matrix
• glomerular endothelial cells
• kidney transplantation
• proximal tubule
• renal biopsy

• amyloidosis
• laser capture dissection
• proteomics

• amyloid
• immunohistochemistry
• mass spectrometry
• proteomics

Hereditary fibrinogen Aα-chain (AFib) amyloidosis is a relatively uncommon renal disease associated with a small number of pathogenic fibrinogen Aα (FibA) variants; wild-type FibA normally does not result in amyloid deposition. Proteomics is now routinely used to identify the amyloid type in clinical samples, and we report here our algorithm for identification of FibA in amyloid.

Proteomics data from 1001 Congo red–positive patient samples were examined using the Mascot search engine to interrogate the Swiss-Prot database and generate protein identity scores. An algorithm was applied to identify FibA as the amyloid protein based on Mascot scores. FibA variants were identified by appending the known amyloidogenic variant sequences to the Swiss-Prot database.

AFib amyloid was identified by proteomics in 64 renal samples based on the Mascot scores relative to other amyloid proteins, the presence of a pathogenic variant, and coverage of the p.449-621 sequence. Contamination by blood could be excluded from a comparison of the FibA score with that of the fibrinogen β and γ chains. The proteomics results were consistent with the clinical diagnosis. Four additional renal samples did not fulfill all the criteria using the algorithm but were adjudged as AFib amyloid based on a full assessment of the clinical and biochemical results.

AFib amyloid can be identified reliably in glomerular amyloid by proteomics using a score-based algorithm. Proteomics data should be used as a guide to AFib diagnosis, with the results considered together with all available clinical and laboratory information.

• amyloid
• amyloidosis
• fibrinogen
• mass spectrometry
• proteomics

• Decellularization
• ECM hydrogel
• Embryo culture
• Endometrium
• Tissue engineering

• Animals
• Embryo, Mammalian
• Embryonic Development
• Endometrium/cytology
• Extracellular Matrix/chemistry
• Extracellular Matrix/transplantation
• Female
• Models, Biological
• Rabbits
• Tissue Scaffolds/chemistry

• Amyloidosis
• formalin
• immunoglobulin
• proteomics
• transthyretin
• variant