Biomedical subjects

Yukio Ando

Publications and source records attributed to Yukio Ando.

At least 19 recordsLinked to original sources

PubMed2006

A transgenic rat with the human ATTR V30M: a novel tool for analyses of ATTR metabolisms.

Amyloidogenic transthyretin (ATTR) is the pathogenic protein of familial amyloidotic polyneuropathy (FAP). To establish a tool for analyses of ATTR metabolisms including after liver transplantations, we developed a transgenic rat model expressing human ATTR V30M and confirmed expressions of human ATTR V30M in various tissues. Mass spectrometry for purified TTR revealed that rat intrinsic TTR and human ATTR V30M formed tetramers. Congo red staining and immunohistochemistry revealed that nonfibrillar deposits of human ATTR V30M, but not amyloid deposits, were detected in the gastrointestinal tracts of the transgenic rats. At 24h after liver transplantation, serum human ATTR V30M levels in transgenic rats that received livers from normal rats became lower than detectable levels. These results thus suggest that this transgenic rat may be a useful animal model which analyzes the metabolism of human ATTR V30M including liver transplantation studies.

Amyloid Neuropathies, Familial↗

PubMed2006

FK506 inhibits murine AA amyloidosis: possible involvement of T cells in amyloidogenesis.

OBJECTIVE: To determine the possibility that T cells represent a potential target for therapy in AA amyloidosis. METHODS: AA amyloidosis was induced in C3H/HeN mice by concomitant administration of AgNO3 and amyloid-enhancing factor (AEF). Mice injected with AgNO3 and AEF received intraperitoneal injections of FK506 (2-200 microg/day). The degree of splenic amyloid deposition was determined by Congo red staining. Serum amyloid A (SAA), interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-a concentrations were measured by ELISA. AA amyloidosis was also induced in ICR mice by injection of Freund's complete adjuvant (FCA) and Mycobacterium butyricum without AEF. ICR mice injected with FCA and M. butyricum also received intraperitoneal injections of FK506 (200 microg/day) to eliminate the possibility that FK506 action might depend upon AEF activity in the amyloid formation. Amyloid deposition was also induced with and without AEF in severe combined immunodeficient (SCID) mice and nude mice to clarify the role of T cells in the mechanism of amyloid formation in AA amyloidosis. RESULTS: FK506 treatment significantly reduced the amount of amyloid deposition and incidence of amyloidosis without reducing serum SAA and proinflammatory cytokine levels in the murine AA amyloidosis models with and without AEF. SCID mice and nude mice showed resistance to development of AA amyloidosis. CONCLUSION: Our findings may provide a new therapeutic strategy for amyloidosis. The results suggested that T cells may play an important role in the mechanism of amyloid formation in AA amyloidosis.

Amyloidosis↗

PubMed2006

Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils.

We have investigated the structure of in vivo formed transthyretin (TTR) amyloid deposits by using antisera raised against short linear sequences of the TTR molecule. In immunohistochemistry, antisera anti-TTR41-50 and anti-TTR115-124-a reacted specifically with both wildtype ATTR and ATTR V30M material, whereas only anti-TTR41-50 recognized ATTR Y114C material. Similar results were obtained by ELISA analysis of ATTR V30M and ATTR Y114C vitreous amyloid, where the anti-TTR115-124-a antiserum failed to react with ATTR Y114C material. Moreover, neither of the antisera recognized natively structured TTR present in pancreatic alpha cells. Our results strongly indicate that the TTR molecule undergoes structural changes during fibrillogenesis in vivo. The finding of a structural difference between wildtype ATTR and ATTR V30M material on one hand and ATTR Y114C material on the other suggests that the fibril formation pathway of these ATTR variants may differ in vivo.

Amino Acid Sequence↗

PubMed2006

Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant.

The mechanism of amyloid formation in familial amyloidotic polyneuropathy (FAP), a hereditary disorder associated with mutant transthyretin (TTR), is still unknown. It is generally believed that altered conformations exposing cryptic regions are intermediary steps in this mechanism. A TTR mutant--Y78F (transthyretin mutant with phenylalanine replacing tyrosine at position 78)--designed to destabilize the native structure has been shown to expose a cryptic epitope recognized by a monoclonal antibody that reacts only with highly amyloidogenic mutants presenting the amyloid fold or with amyloid fibrils. To test whether TTR deposition in FAP can be counteracted by antibodies for cryptic epitopes, we immunized with TTR Y78F, transgenic mice carrying the most common FAP-associated TTR mutant--V30M (transthyretin mutant with methionine replacing valine at position 30)--at selected ages that present normally with either nonfibrillar or TTR amyloid deposition. Compared to age-matched control nonimmunized mice, Y78F-immunized mice had a significant reduction in TTR deposition usually found in this strain, in particular in stomach and intestine; by contrast, animals immunized with V30M did not show differences in deposition in comparison with nonimmunized mice. Immunohistochemical analyses of tissues revealed that immunization with Y78F lead to infiltration by lymphocytes and macrophages at common deposition sites, but not in tissues such as liver, choroid plexus, and Langerhans islets, in which TTR is produced. These results suggest that Y78F induced production of an antibody that reacts specifically with deposits and leads to an immune response effective in removing/preventing TTR deposition. Therefore, TTR immunization with selected TTR mutants has potential application in immune therapy for FAP.

Amyloid Neuropathies, Familial↗

PubMed2006

Lipid droplets are present in amyloid deposits in familial amyloidotic polyneuropathy and dialysis related amyloidosis.

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.

Adult↗

PubMed2006

Aging and transthyretin-related amyloidosis: pathologic examinations in pulmonary amyloidosis.

Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 +/- 8.75 vs. 39.75 +/- 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M.

Adult↗

PubMed2006

Analysis of amyloid fibrils in the cheetah (Acinonyx jubatus).

Recently, a high prevalence of amyloid A (AA) amyloidosis has been documented among captive cheetahs worldwide. Biochemical analysis of amyloid fibrils extracted from the liver of a Japanese captive cheetah unequivocally showed that protein AA was the main fibril constituent. Further characterization of the AA fibril components by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis revealed three main protein AA bands with approximate molecular weights of 8, 10 and 12 kDa. Mass spectrometry analysis of the 12-kDa component observed in SDS-PAGE and Western blotting confirmed the molecular weight of a 12,381-Da peak. Our finding of a 12-kDa protein AA component provides evidence that the cheetah SAA sequence is longer than the previously reported 90 amino acid residues (approximately 10 kDa), and hence SAA is part of the amyloid fibril.

Acinonyx↗

PubMed2006

Effect of tacrolimus and partial hepatectomy on transthyretin metabolism in rats.

Liver transplantation, which serves as treatment of familial amyloidotic polyneuropathy (FAP), and domino liver transplantation, which utilizes resected livers from patients with FAP for treatment of liver diseases, may induce changes in transthyretin (TTR), a pathogenic FAP-related protein. To evaluate this possibility, we performed a 70% hepatectomy or administered tacrolimus to Dark Agouti (DA) rats for 7 days and then measured changes in liver TTR mRNA levels and changes in serum TTR concentrations. After hepatectomy, TTR mRNA levels decreased by 77%; at day 3, they returned to preoperative levels. Except for slightly elevated serum TTR concentrations 12 h after operation, serum TTR levels remained unchanged. Thus, partial hepatectomy did not influence serum TTR concentrations. After tacrolimus administration, TTR mRNA declined by 56% 12 h after the experiment started; however, after day 3, a rebound phenomenon occurred until day 7. Tacrolimus may facilitate serum TTR degradation, although production of TTR in the liver also increased. This finding -- that TTR, the source of FAP-inducing amyloid, did not increase after transplantation -- may help post-transplantation treatment of patients who have FAP and other liver diseases.

Animals↗

PubMed2006

Severe congestive heart failure with cardiac liver cirrhosis 10 years after orthotopic liver transplantation for familial amyloidotic polyneuropathy.

Reported herein is an autopsy case of familial amyloidotic polyneuropathy (FAP) with cardiac liver cirrhosis associated with amyloid cardiomyopathy after liver transplantation. At 47 years of age a Japanese woman with a transthyretin Val30Met mutation and sensorimotor polyneuropathy underwent liver transplantation; no postoperative deterioration related to the graft or polyneuropathy occurred. However, cardiovascular dysfunction associated with amyloid deposition gradually worsened. Pacemaker implantation and diuretics were ineffective against the heart failure; 10 years after transplantation the patient died. Autopsy revealed massive pleural and pericardial effusions and amyloid cardiomyopathy, especially in the right atrium and cardiac conduction system. Amyloid deposition was slight in all organs except the heart, but liver cirrhosis with reversed lobulation and centrilobular hemorrhagic necrosis was prominent. There was no histological evidence for chronic liver graft rejection. These findings suggest that liver transplantation effectively stopped amyloid deposition and ameliorated clinical FAP symptoms but that amyloid cardiomyopathy after liver transplantation in advanced clinical stages may lead to severe congestive heart failure and cardiac liver cirrhosis.

Adult↗

PubMed2006

Lower urinary tract dysfunction in type 1 familial amyloidotic polyneuropathy in Kumamoto, Japan.

OBJECTIVE: To evaluate lower urinary tract dysfunction of type 1 familial amyloidotic polyneuropathy (FAP) patients in Kumamoto, Japan. METHODS: Lower urinary tract symptoms were evaluated in FAP patients. Urodynamic studies were evaluated in FAP patients as compared to those in control subjects. The location and distribution of amyloid deposits were evaluated in the urinary bladder in an autopsy case. RESULTS: In lower urinary symptoms, 86%, 19% and 38% patients showed difficulty in urination, urinary frequency and urinary incontinence. In detrusor function during filling cystometry, 14% patients showed detrusor overactivity. Moreover, 43% patients showed low compliance bladder, 62% and 38% patients showed normal and reduced bladder sensation, respectively. First desire to void (FDV), strong desire to void (SDV) and post-voided residual urine (PVR) were increased in FAP patients as compared to those in control subjects. In the urethral pressure profilometry, 71%, 10% and 19% patients showed incompetent, normal functional and overactive urethral closure mechanism, respectively. Maximum urethral pressure (MUP), maximum urethral closure pressure (MUCP) and functional profile length (FPL) were decreased in FAP patients compared to those in control subjects. CONCLUSION: Autonomic, somatic nerve systems and bladder detrusor musculature might be impaired in lower urinary tract of type 1 FAP patients in Kumamoto, Japan.

Adult↗

PubMed2006

Transthyretin RNA profiling in livers from transplanted patients affected by familial amyloidotic polyneuropathy, and identification of a dual transcription start point.

Mutations in the transthyretin (TTR) gene cause familial amyloidotic polyneuropathy (FAP), an autosomal dominant peripheral neuropathy, often associated with cardiomyopathy. Liver transplant currently represents a powerful therapeutic approach for FAP patients, although its efficacy is heavily dependent both on the disease severity and on the cardiac functionality. We have investigated the TTR gene expression searching for tissue-specific additional messengers in human adult and foetal tissues as well as in eight livers from FAP transplanted patients carrying different TTR mutations (Met30, Pro36, Ala47, Arg50, and Gln89). We identified a novel transcript, recognising a different transcription start site. The additional 5'-UTR sequence of this novel transcript contains regulatory boxes possibly highlighting an additional transcription start point. RNA analysis revealed that this region is represented in all foetal/adult tissues analysed. We discussed the implications of this finding which might provide perspectives for better understanding the TTR gene expression.

Amyloid Neuropathies, Familial↗

PubMed2006

[Transthyretin-its function and pathogenesis].

Transthyretin (TTR) is a transport protein for retinol-binding protein and thyroxin, and works as a rapid turnover protein. Recently, it has been used as a nutrition assessment protein in the assessment of the acute phase nutritional status in various diseases because it contains four tryptophans in the tetramer of the protein and its plasma half life is 1.9 days. However, the wild-type protein and its mutated form become a precursor protein of amyloid fibrils in senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy(FAP), respectively. Recent biochemical and pathological studies revealed that instability of the terameric form of TTR by mutation and post-translational modifications leads to amyloid formation in the tissues of SSA and FAP. In the process of TTR amyloid formation, misfolding of TTR, the trigger of amyloid formation, is also induced. For these amyloid formation mechanisms, Cr3+ administration, BSB(FSB) therapy, gene therapy, and antibody therapy are now on-going therapeutic projects for FAP and SSA.

Amyloidosis↗

PubMed2006

[Application to transthyretin analysis].

Transthyretin (TTR) is the precursor protein of familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis (SSA). TTR-related FAP is a hereditary amyloidosis induced by mutated TTR. The most common type of FAP is FAP amyloidogenic TTR (ATTR) Val30Met: TTR substitution of methionine for valine at position 30 of the TTR sequence. In this type of FAP, amyloid deposition causes organ failure including peripheral neuropathy, autonomic disorders, gastrointestinal symptoms, and cardiac and renal failure. In Japan, it is well known that Kumamoto and Nagano are the two major foci of FAP, but recently, FAP has been found throughout Japan. In addition, various different types of mutations in the TTR gene and phenotypes of FAP have also been documented. Medical care for FAP is becoming more important. Detection of mutant TTR is indispensable to diagnose the disease in order to treat FAP. We have developed a method for detecting mutant TTR in serum and cerebrospinal fluid by means of mass spectrometry to screen for variant TTR in FAP patients. In this article, we reviewed the general characteristics of TTR and clinical features of FAP, and described the identification of mutant TTR using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS). In addition, we analyzed TTR modifications and protein profiles in serum samples of Japanese and Swedish patients using SELDI-TOF-MS to look for a key protein(s) as a trigger of FAP.

Amyloid Neuropathies, Familial↗

PubMed2006

[Introduction of Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University].

Pathologic informatics is an analysis of mechanism of pathogenesis using various medical information. Biologic reactions by many reactants are studied on molecules, cells, organs, and individuals by using various methods. Themes of our laboratory are as follows: 1) to analyze of the pathogenesis of various diseases by using novel diagnostic methods, 2) to elucidate amyloid formation mechanism in amyloidosis and to develop novel therapies, 3) to develop the methods for tests and diagnosis for DIC, 4) to study on activation mechanism of ribosomal proteins in the tissues by the blood cell function, 5) to study on the expression and suppression of neogenesis of blood vessels by physical invasion in the organ failure, and 6) to develop the diagnostic methods for autonomic dysfunction and to analyze the pathogenesis.

Amyloidosis↗

PubMed2005

Chromium(III) ion and thyroxine cooperate to stabilize the transthyretin tetramer and suppress in vitro amyloid fibril formation.

Transthyretin (TTR) amyloid fibril formation, which is triggered by the dissociation of tetrameric TTR, appears to be the causative factor in familial amyloidotic polyneuropathy and senile systemic amyloidosis. Binding of thyroxine (T(4)), a native ligand of TTR, stabilizes the tetramer, but the bioavailability of T(4) for TTR binding is limited due to the preferential binding of T(4) to globulin, the major T(4) carrier in plasma. Here, we show that Cr(3+) increased the T(4)-binding capacity of wild-type (WT) and amyloidogenic V30M-TTR. Moreover, we demonstrate that Cr(3+) and T(4) cooperatively suppressed in vitro fibril formation due to the stabilization of WT-TTR and V30M-TTR.

Amyloid↗

PubMed2005

Ocular amyloid angiopathy associated with familial amyloidotic polyneuropathy caused by amyloidogenic transthyretin Y114C.

PURPOSE: To report the clinicopathological findings for a unique ocular amyloid angiopathy in patients with familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin Y114C. DESIGN: Three case reports. METHODS: Retrospective review of clinicopathological findings, course, and treatment of the 3 patients. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure, fundus photography, fluorescein angiography (FA), indocyanine green angiography, and histopathological analysis. RESULTS: In the 32-year-old patient, in the early stage of FAP, indocyanine green angiography demonstrated multiple sites of hyperfluorescence, with staining along major choroidal veins. Retinal vessels appeared normal clinically and on FA. In the 48-year-old patient, who had late-stage FAP, examination of the fundus revealed pinpoint white amyloid opacities over the retinal surface, sheathing of retinal vessels, and scattered retinal hemorrhages. Fluorescein angiography showed vascular closure, focal staining, and microaneurysms. Indocyanine green angiography revealed multiple sites of hyperfluorescence, with staining along retinal and choroidal vessels. Examination during follow-up revealed that these vascular changes continued to progress. Histopathological study of an eye obtained at autopsy from the 49-year-old patient revealed marked intravascular and extravascular amyloid deposition. CONCLUSIONS: Severe and progressive amyloid angiopathy causing visual disturbance was seen in patients with FAP caused by amyloidogenic transthyretin Y114C.

Adult↗

PubMed2005

Effect of nitric oxide in amyloid fibril formation on transthyretin-related amyloidosis.

Although oxidative stress is said to play an important role in the amyloid formation mechanism in several types of amyloidosis, few details about this role have been described. Amyloid is commonly deposited around the vessels that are the primary site of action of nitric oxide generated from endothelial cells and smooth muscle cells, so nitric oxide may be also implicated in amyloid formation. For this study, we examined the in vitro effect of S-nitrosylation on amyloid formation induced by wild-type transthyretin, a precursor protein of senile systemic amyloidosis, and amyloidogenic transthyretin V30M, a precursor protein of amyloid deposition in familial amyloidotic polyneuropathy. S-Nitrosylation of amyloidogenic transthyretin V30M via the cysteine at position 10 was 2 times more extensive than that of wild-type transthyretin in a nitric oxide-generating solution. Both wild-type transthyretin and amyloidogenic transthyretin V30M formed amyloid fibrils under acidic conditions, and S-nitrosylated transthyretins exhibited higher amyloidogenicity than did unmodified transthyretins. Moreover, S-nitrosylated amyloidogenic transthyretin V30M formed more fibrils than did S-nitrosylated wild-type transthyretin. Structural studies revealed that S-nitrosylation of amyloidogenic transthyretin V30M induced a change in its conformation, as well as instability of the tetramer conformation. These results suggest that the nitric oxide-mediated modification of transthyretin, especially variant transthyretin, may play an important role in amyloid formation in senile systemic amyloidosis and familial amyloidotic polyneuropathy.

Amino Acid Substitution↗

PubMed2005

CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition, hallucinations in 71% of affected patients, and delusions in 57% were also described. Our findings in this family suggest that a specific NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.

Adult↗