ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity.

Amyloidogenic transthyretin (ATTR) amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin. Transthyretin is primarily produced in tetrameric form by the liver, but also by retinal epithelium and choroid plexus. The deposition of these fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant.

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable.

Post-translational modification of amyloid a protein in patients with AA amyloidosis.

AA amyloidosis is a disease caused by extracellular deposition of insoluble β-pleated sheet fibrils composed of amyloid A (AA) protein, an amino (N)-terminal fragment of serum amyloid A (SAA). The deposits disrupt tissue structure and compromise organ function. Although the disease is systemic, deposition in kidney glomeruli is the most common manifestation.

A transgenic mouse model reproduces human hereditary systemic amyloidosis.

Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein.

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of studies, these fragments have been proposed to play important roles in amyloid formation.

Carbamylation of the amino-terminal residue (Gly1) of mouse serum amyloid A promotes amyloid formation in a cell culture model.

Amyloid A (AA) amyloidosis is a fatal protein deposition disease afflicting a small percentage of patients with chronic inflammation. Factors other than inflammation that determine development of AA amyloidosis remain largely unknown. The subunit protein comprising AA amyloid fibrils is derived from serum amyloid A (SAA), specifically its amino-terminal portion.

Hereditary systemic immunoglobulin light-chain amyloidosis.

Several members of a family died from renal failure as a result of systemic amyloidosis. Extensive studies to detect previously documented gene mutations associated with amyloidosis failed to identify a causative factor. In search of the genetic basis for this syndrome, amyloid fibrils were isolated from renal tissue of a member of the kin who died while on renal dialysis.

Characterization of rat serum amyloid A4 (SAA4): a novel member of the SAA superfamily.

The serum amyloid A (SAA) family of proteins is encoded by multiple genes, which display allelic variation and a high degree of homology in mammals. The SAA1/2 genes code for non-glycosylated acute-phase SAA1/2 proteins, that may increase up to 1000-fold during inflammation. The SAA4 gene, well characterized in humans (hSAA4) and mice (mSaa4) codes for a SAA4 protein that is glycosylated only in humans.

Human SAA1-derived amyloid deposition in cell culture: a consistent model utilizing human peripheral blood mononuclear cells and serum-free medium.

Amyloid A (AA) amyloidosis is a fatal disease caused by extracellular deposition of fibrils derived from serum AA (SAA). AA amyloid fibril formation has previously been modeled in macrophage cultures using highly amyloidogenic mouse SAA1.1, but attempts to do the same with human SAA invariably failed.

Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis.

AA amyloid patients who experience disease progression and develop renal failure have not received sufficient benefit from agents that treat inflammation or infection. We have begun to explore the potential application of antisense oligonucleotides (ASOs) to specifically suppress SAA production and thereby reduce amyloid deposition. Proof-of-concept experiments conducted in mice initially examined ASO ability to reduce serum levels of SAA during an acute inflammatory response.

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells.

Serum amyloid A protein (SAA), a prominent component of the acute-phase response, is strongly expressed in developing and repairing kidneys and promotes tubulogenesis. Accordingly, we reprogrammed relatively undifferentiated NRK52E cells with the mouse SAA1.1 gene and transplanted SAA-positive and -negative cells into rats with acute renal failure.

Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment.

Leptomeningeal amyloidosis associated with mutations in transthyretin (TTR) is a rare but fatal form of amyloidosis. Dementia and intracerebral haemorrhage are prominent features of this disease for which no specific therapy is known. In previous studies, we have shown that antisense oligonucleotides (ASOs) specific for human TTR could inhibit hepatic synthesis of TTR in mice transgenic for a human amyloid-associated TTR and may offer a medical means of treating systemic TTR amyloidosis.

Acute-phase response protein serum amyloid A stimulates renal tubule formation: studies in vitro and in vivo.

Serum amyloid A protein (SAA) surges 1,000-fold in the blood of acute-phase animals, and yet its function during these acute events remains unknown. We report herein that SAA stimulates a developmental program in cultured NRK-52E cells that culminates in differentiated and functional tubules that feature a proximal tubule phenotype. We also found strong SAA expression in states of tubule formation (in utero stage) and regeneration (recovery from ischemia-reperfusion injury).

Cellular events associated with the initial phase of AA amyloidogenesis: insights from a human monocyte model.

Reactive amyloidosis is a systemic protein deposition disease that develops in association with chronic inflammation. The deposits are composed of extracellular, fibrillar masses of amyloid A (AA) protein, an N-terminal fragment of the acute-phase serum protein serum amyloid A (SAA). The pathogenic conversion of SAA into amyloid has been studied in two human cell culture models, peritoneal cells and peripheral blood monocytes.

Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis.

We previously reported that heterozygous DNA methyltransferase 1-deficient (Dnmt1(+/-)) mice maintain T-cell immune function and DNA methylation levels with aging, whereas controls develop autoimmunity, immune senescence, and DNA hypomethylation. We therefore compared survival, cause of death, and T-cell DNA methylation gene expression during aging in Dnmt1(+/-) mice and controls. No difference in longevity was observed, but greater numbers of Dnmt1(+/-) mice developed jejunal apolipoprotein AII amyloidosis.

Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides.

Transthyretin (TTR) amyloidosis, the most common form of hereditary systemic amyloidosis, is characterized clinically by adult-onset axonal neuropathy and restrictive cardiomyopathy. More than 85 mutations in transthyretin have been found to cause this hereditary disease. Since essentially all circulating TTR is of hepatic origin, orthotopic liver transplantation has been used as the only specific form of therapy.

Renal transplantation for apolipoprotein AII amyloidosis.

Apolipoprotein AII (ApoAII) amyloidosis, first reported in 2001 in a family with renal amyloidosis, is associated with mutations in the stop codon of the apolipoprotein AII gene resulting in a carboxyl terminal peptide extension of 21 amino acid residues in the protein. Since death from this form of amyloidosis is due to renal failure, kidney dialysis and renal transplantation are presently the only two therapeutic options. We report the case of a Caucasian man who developed proteinuria in his late 20's, had renal biopsy at the age of 33 which gave the diagnosis of renal amyloidosis, and required continuous ambulatory peritoneal dialysis by age 45.

A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis.

Background: More than 80 transthyretin (TTR) mutations have been described, most associated with amyloidosis. Peripheral neuropathy is the most common clinical presentation in TTR amyloidosis although the carpal tunnel syndrome (CTS) may be the first symptom and skin can be involved, as transthyretin amyloidosis is a systemic disease.

Case Report: The 78 year-old proband, belonging to a French family of Italian origin, presented with a 5 year history of peripheral neuropathy in the lower extremities.

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians.

Serum amyloid A1 (SAA1), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAA1 exon 3 polymorphisms and susceptibility to amyloidosis.

Amyloid-enhancing factor mediates amyloid formation on fibroblasts via a nidus/template mechanism.

Objective: To determine the mechanism by which amyloid-enhancing factor (AEF) promotes amyloid deposition, and to test whether AEF seeds deposition of serum amyloid A (SAA) and facilitates conversion to beta-sheet structure.

Methods: Fibroblasts were cultured with mouse recombinant SAA1.1 and AEF, SAA1.