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Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits-positive for both ATTR and AApoAI-was significantly thicker than that of patients who had LSCS with single-positive-that is, positive for either ATTR or AApoAI-amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS.

Amyloidosis is an extremely rare event in rats. In this study, we report that lipopolysaccharide binding protein (LBP) is the most likely amyloidogenic protein in rat mammary amyloidosis. Histologically, corpora amylacea (CA) and stromal amyloid (SA) were observed in rat mammary glands, and needle-shaped amyloid (NA) was also observed on the surface or gap of CA and SA. Following surveillance in aged rats, NA was observed in 62% of mammary tumours, 25% of male mammary glands and 83% of female mammary glands. Proteomic analysis showed that lactadherin was a major constitutive protein of CA and SA, and both were positive following immunohistochemistry with anti-lactadherin antibodies. In the same analysis, LBP was detected as a prime candidate protein in NA, and NA was positive following immunohistochemistry and immunoelectron microscopy with anti-LBP antibody. Furthermore, synthetic peptides derived from rat LBP formed amyloid fibrils in vitro. Overall, these results provide evidence that LBP is an amyloid precursor protein of NA in rat mammary glands.

Intracellular aberrant protein aggregation is linked to the mechanism of Parkinson’s disease (PD). Autonomic dysfunction is commonly found because α-synuclein aggregate in autonomic nerves in patie...

Little is known in mechanism and clinical features of transient focal neurological episodes (TFNEs) in patients with both hereditary transthyretin (ATTR) type and Aβ-type cerebral amyloid angiopath...

Insulin-derived amyloidosis is a complication of insulin therapy. The amyloid fibril protein is derived from the injected insulin and forms an amyloid deposit at the injection site [1,2]. The clini...

Transthyretin familial amyloid polyneuropathy (ATTR-FAP) is a fatal hereditary amyloidosis characterized by extracellular deposition of amyloid fibrils composed of transthyretin (TTR) [1,2]. Tafami...

Although there is growing evidence suggesting the involvement of oxidative stress in neurological disorders [1], evidence of oxygen-mediated damage in neuropathy due to ATTR-PN remains to be discus...

Hereditary transthyretin (TTR) amyloidosis is characterized by ATTR amyloid deposits in various tissue sites and organs, such as peripheral nerves, heart, gastrointestinal tract, kidneys, eyes, and...

Domino liver transplantation (DLT) using liver grafts from patients with hereditary transthyretin (TTR) amyloidosis has been performed because of a severe liver graft shortage. Some of DLT recipien...

Liver transplantation (LT) reportedly prolonged the survival of hereditary transthyretin (TTR) amyloidosis patients [1,2]. However, duration from disease onset to death in late-onset hereditary TTR...

Localized amyloidosis of the genitourinary tract is uncommon and an extremely rare cause of hydronephrosis and renal failure. Monge et al. [1] reviewed 169 reported cases of localized amyloidosis o...

Immunohistochemistry (IHC) is usually used to identify the amyloid precursor protein. However, the results may be inconclusive owing to a loss of epitopes or small amounts of amyloid deposits, comp...

Liver transplantation halts production of mutated transthyretin (TTR), and thus it is an accepted treatment, with improved survival, in patients with hereditary (familial) amyloidosis with polyneuropathy (FAP). However, the effects of transplantation on the clinical manifestations of FAP have not yet been adequately clarified. This study aimed to investigate whether liver transplantation would improve the long-term clinical manifestations in FAP patients who had undergone transplantations.We assessed 29 non-transplant and 36 transplant FAP V30M patients using an FAP clinical scoring system.The total clinical score of the non-transplant group increased and was significantly correlated with FAP duration; that of the transplant group increased slowly after transplantation. In patients 5 years or more after FAP onset, the total clinical scores of the transplant group were significantly lower than those of the non-transplant group. In the same patients, scores for sensory, motor, autonomic and organ impairments of the transplant group were significantly lower than those of the non-transplant group.Liver transplantation had beneficial effects on FAP clinical manifestations in patients with FAP TTR V30M. Liver transplantation should therefore be considered as an effective treatment in the clinical management of patients with FAP TTR V30M.

The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.

Background Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls. Methods Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee. Results The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively). Conclusions A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.

VIIIth International Symposium on Familial Amyloidotic Polyneuropathy (FAP) and VIIth International Symposium on Liver transplantation in FAP were held in Kumamoto November 19–22, 2011. As the sate...

It is well known that autonomic dysfunction in familial amyloidotic polyneuropathy (FAP) is the most serious problem, because it restricts the daily life of these patients. The detail mechanisms of the onset are not well understood in FAP and domino liver transplantation-induced amyloid neuropathy. As autonomic disturbances play an important role in the symptomatology of FAP, further studies of autonomic dysfunction in these patients may lead the pathogenesis of FAP. Autonomic dysfunction is often observed before sensory and motor nerve dysfunction in FAP. This can be attributed to the morphological characteristics of the nerves. Unmyelinated, small myelinated, and large myelinated fibers tend to become impaired in that order. Although the reasons of susceptibility to amyloid infiltration and injury are not known, studies of autopsied FAP patients have revealed heavy infiltration of amyloid in autonomic ganglions. Moreover, spinal ganglion and posterior loot of the spine had severe amyloid deposits than did the anterior root of the spine or the motor nerves. It is well known that autonomic dysfunction is the most serious problem, because it restricts the daily life of FAP patients. However, we have four major questions about autonomic dysfunction in clinical. In this manuscript, we discuss about the answers of these questions.

The status of domino liver transplantation (DLT) in Japan was evaluated. DLT and familial amyloidotic polyneuropathy (FAP) recipients who underwent living donor liver transplantation (LDLT) at Kumamoto University were reviewed with attention to surgical procedures. Thirty-nine DLTs were performed in Japan until 2010, and survival rates at 1 and 3 years were 82% and 63.6%, respectively. Six of 21 DLT recipients who survived for more than 3 years developed amyloid depositions within organs, and de novo amyloid neuropathy was reported in three patients. DLT from FAP recipients in Kumamoto was safely performed with preservation of the retrohepatic inferior vena cava in FAP recipients. All 20 FAP recipients who were DLT donors are alive with the exception of one who died of the original FAP 9 years after LDLT. The outcomes of DLT and FAP recipients in Kumamoto were satisfactory.

Familial amyloidotic polyneuropathy (FAP) is a protein folding disorder that induces neuropathy and cardiomyopathy, leading to death within 7-15 years after onset of clinical disease. In vitro, small ligands binding the thyroid hormone docking site stabilize tetrameric transthyretin, inhibiting amyloid fibril formation. We undertook a randomized, placebo-controlled clinical trial to determine whether diflunisal, a well-known non-steroidal anti-inflammatory drug (NSAID) alters neurologic disease progression in FAP. We enrolled 130 subjects with wide age and FAP mutation representation. To date, few recognized complications of NSAIDs have occurred in the study cohort. Data collection will be completed by November 2012.

Pathological studies of FAP showed that TTR amyloid demonstrates organ and tissue tropism, and therefore, the mechanism of TTR fibril formation is thought to be closely related to the microenvironment in which amyloid fibrils form. However, many key issues, including the precise site of amyloid fibril formation and the effect of amyloid deposition on cells and tissues, remain largely unknown. In this study, we analyzed the relationship between amyloid fibril formation and extracellular matrix. Histopathological analyses showed an increase in the amount of the major components of the extracellular matrix with TTR amyloid deposition. In vitro studies also showed that TTR aggregates had a bioactivity to induce up-regulation of these extracellular matrix components. To know the precise mechanism of this up-regulation may lead to deeper understanding of FAP pathogenesis.

This study investigated whether transplantation improves the long-term outcome of transplanted Japanese patients with familial amyloid polyneuropathy (FAP) by comparing their long-term su...

Senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR) is a prevalent disorder in the elderly. However, mechanisms of WT TTR amyloid formation and risk factors for...

To elucidate the effect of liver transplantation on changes in clinical manifestations, amount of amyloid deposition, and biochemistry of amyloid fibrils in the heart of familial amyloid ...

Although in Western countries the prevalence of senile systemic amyloidosis (SSA) in the elderly (>80 years) was found to be about 25% based on examination of autopsy-derived cardiac spec...

It is not fully understood what kind of biologics targeting inflammatory cytokines is the most effective therapeutic agent for amyloid A (AA) amyloidosis. Moreover, biologics targeting in...

Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Di ...

Activation of fibrinolysis system and excessive fibrinolysis are observed in monoclonal antibody light chain (AL)-amyloidosis. However, the mechanisms by which activation of fibrinolysis occurs in AL-amyloidosis have not been fully elucidated. To determine whether urokinase type-plasminogen activator (uPA), an important activator of fibrinolytic system, contributes to the activation of fibrinolytic system in AL-amyloidosis, we immunohistologically examined uPA in bone marrow plasma cells. More than 90% of bone marrow plasma cells from five different AL-amyloidosis patients were uPA-positive as examined with immunohistochemical staining. All the bone marrow plasma cells from seven different patients with multiple myeloma were uPA-negative. A patient with AL-amyloidosis, who had bleeding diathesis and excessive fibrinolysis with hypofibrinogenemia, was treated with nafamostat mesilate, a potential inhibitor of uPA. After the administration of nafamostat mesilate, the bleeding diathesis disappeared, and excessive fibrinolysis and hypofibrinogenemia were improved. The present data suggested that uPA expressed in plasma cells may have contributed to the pathogenesis of excessive fibrinolysis.

A 68-year-old Italian woman who had a clinical history of thyroidectomy in 2002 presented with slowly progressing renal insufficiency and non-nephrotic proteinurea in 2004. A renal biopsy showed the occurrence of amyloid; the thyroid biopsy previously taken also revealed amyloid infiltration. Other amyloid-containing tissues included bone marrow and heart. The plasma cell level in the bone marrow was found to be less than 5% and both serum and urine samples were positive for a monoclonal kappa light chain band. DNA analysis unexpectedly revealed the presence of a novel transthyretin (TTR) mutation, ATTR Asn124Ser. Histologically, amyloid deposits in the thyroid had a homogeneous appearance with moderate Congophilia. In immunohistochemistry, a kappa light chain antiserum showed positive immunoreactivity with amyloid deposits in the thyroid. Furthermore, a TTR antiserum, anti-TTR50-127, also recognized a number of amyloid deposits stained positive with the kappa light chain antiserum. Overall, the kappa light chain antiserum reacted with most of the amyloid deposits in the thyroid, whereas TTR immunoreactivity was scarcer, with a scattered appearance. In contrast, only the anti-TTR50-127 antiserum labeled amyloid in the kidney, albeit not all deposits. In this study, we report a patient having a novel TTR variant, ATTR Asn124Ser, with co-localization of kappa light chains in the amyloid deposits in the thyroid tissue.

It has been well documented that transthyretin (TTR) shows an affinity for lipoproteins and amyloid is deposited around adipocytes in patients with familial amyloidotic polyneuropathy (FAP). We examined the involvement of lipids in amyloid fibrils in the tissues by histopathologic methods. Sudan black B staining for frozen tissues of autopsied FAP patients and biospied dialysis related amyloidosis (DRA) patients revealed colocalization of lipids in the tissue sections where Congo red staining was positive, while no such positive staining was observed in paraffin embedded tissues. Immunohistochemical study using lipoprotein antibodies revealed that only anti-high density lipoprotein (HDL) antibody showed immunoreactivity in both types of amyloid specimens where Congo red was positively stained. Measurement of the components of lipids in the frozen cardiac samples from an FAP patient and an amyotrophic lateral sclerosis (ALS) patient revealed that concentrations of triglyceride and cholesterol in each lipoprotein, except for HDL-triglyceride, were markedly elevated in the FAP patient's material, compared to that of the ALS patient. These results suggest that interaction of amyloid fibrils with HDL may play an important role in amyloid formation in FAP.

Transthyretin (TTR) is a tetrameric protein that can dissociate into amyloidogenic monomers and cause TTR-related amyloidosis. A rare phenotype, called hereditary leptomeningeal TTR amyloidosis, in which TTR amyloid deposition occurs mainly in leptomeninges and subarachnoid vessels, has been reported in patients with several different TTR variants. In the present study, we examined TTR variants immunoprecipitated from the serum and cerebrospinal fluid (CSF) of patients with hereditary leptomeningeal TTR amyloidosis using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (IP-Mass method). The leptomeningeal-type TTR variants were not detected in the serum but were found at low levels in the CSF. The undetectable levels of the leptomeningeal-type TTR variants in serum could explain the minute amounts of systemic deposition of these variants. The relatively high level of unstable TTR variants in CSF, probably due to increased secretion from the choroid plexus, is considered to be the pathogenesis of the leptomeningeal-type of TTR amyloidosis.

To determine the origin of transthyretin (TTR) in the aqueous humor of patients with familial amyloidotic polyneuropathy (FAP), we measured TTR levels and analyzed the TTR forms in the aqueous humor of three FAP patients (one patient; liver transplanted, and two patients; non-transplanted). The total TTR levels were almost the same as reported previously in non-transplanted patients and slightly increased in a transplanted patient. Analyses with mass spectrometry in the two non-transplanted FAP ATTR V30M patients revealed that both wild type and variant TTR forms were detected in their aqueous humor samples. Moreover, variant TTR forms could be detected in the aqueous humor of the transplanted patient while the liver produced no variant TTR. These results suggest that variant TTR in aqueous humor may be derived from retina where TTR was produced. In conclusion, TTR metabolism may occur in its own ocular cycle and variant TTR produced by the retina may play an important role in amyloid formation in the ocular tissues of FAP patients.

Variant forms and post-translational modifications of transthyretin (TTR) can be identified by electrospray ionisation mass spectrometry (ESI-MS). The aim of the present study was to investigate thiol conjugation of transthyretin and it's relation to age and symptomatic amyloid disease in different populations of variant TTR carriers. Plasma samples from 70 individuals from Denmark, Argentina, Sweden and Japan, with 2 different TTR mutations were analysed. The percentage cysteine (Cys) conjugated wild and variant TTR were calculated from the corresponding peaks of the spectra, and multiple regression analysis was employed to disclose relationships between age, symptomatic amyloid disease and origin. Age, origin and presence of symptomatic disease, were found to be independent factors related to transthyretin conjugation. A higher percentage of conjugated to unconjugated TTR was disclosed in symptomatic, but not in asymptomatic carriers. In summary: Thiol conjugation of TTR is dependent on age and presence of symptomatic amyloid disease. Furthermore, it varies between different populations. Variant TTR is more susceptible to thiol conjugation than the wild type. Post-translational factors may be related to amyloid formation and/or toxicity.