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Biomedical subjects

F Kametani

Publications and source records attributed to F Kametani.

At least 19 recordsLinked to original sources
PubMed2006

Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs onto myocardium in FAP patients.

To elucidate whether progressive wild-type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation-mass spectrometry method and liquid chromatography-ion trap mass spectrometry analysis. The ratio of wild-type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild-type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild-type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.

Amyloid Neuropathies, Familial↗
PubMed2001

Human wild presenilin-1 mimics the effect of the mutant presenilin-1 on the processing of Alzheimer's amyloid precursor protein in PC12D cells.

Most familial early-onset Alzheimer's disease (FAD) is caused by mutations in the presenilin-1 (PS1) gene. Abeta 42 is derived from amyloid precursor protein (APP) and increased concentrations are widely believed to be a pathological hallmark of abnormal PS function. Thus, the interaction between PS1 and APP is central to the molecular mechanism of AD. To examine the effect of wild-type human PS1 on rat APP metabolism, we made several PC12D cell lines that expressed human wild or mutant PS1, and analyzed the processing of endogenous rat APP and the intracellular gamma-secretase activity. We found the ratio of Abeta 42/Abeta 40 increased in PC12D cells expressing wild-type human PS1. These changes were identical to those found in PC12D cells expressing human PS1 bearing the A260V mutation. These results suggest that APP metabolism is physiologically regulated by the PS1 and that loss of normal PS1 affects gamma-secretase activity.

Alzheimer Disease↗
PubMed2001

Antigens of monoclonal antibody NB3C4 are novel markers for oligodendrocytes.

We produced NB3C4, a novel monoclonal antibody specific for oligodendrocytes, using human neuroblastoma IMR-32 cells. NB3C4 specifically recognized oligodendrocytes in the CNS, although it bound to neuroblastoma IMR-32 cells and oligodendrocytes in vitro. Double immunofluorescence staining of rat brain using NB3C4 and anti-GST-pi, anti-glial fibrillary acidic protein (GFAP), or anti-neurofilament 200 (NF) antibody revealed that anti-GST-pi antibody identified an oligodendrocyte marker recognizing NB3C4-positive cells, while both anti-GFAP and anti-NF antibody did not. Western blotting of rat brain homogenates showed that NB3C4 bound three proteins of 22-28 kDa, while the anti-GST-pi recognized a 27 kDa protein. Therefore, antigens recognized by NB3C4 could be novel markers for oligodendrocytes.

Animals↗
PubMed2001

Serum transthyretin monomer in patients with familial amyloid polyneuropathy.

Although dissociation of the transthyretin (TTR) tetramer is suspected of being the first step in amyloid fibril formation in hereditary TTR amyloidosis, including familial amyloid polyneuropathy (FAP), the TTR monomer has never been examined in vivo. Therefore, we analyzed the TTR monomer in the serum of FAP patients and normal individuals. Free TTR monomer was detected in both groups using gel filtration chromatography and immunoblotting. Both the mean concentration of free TTR monomer and the total serum TTR were significantly lower in FAP patients than in normal individuals. Moreover, in FAP patients, mass spectrometry showed that the variant TTR monomer was markedly decreased compared with the wild-type TTR monomer. These findings suggest that the free variant TTR monomer is unstable in serum, and that it aggregates in deposits in various organs or is adsorbed by preexisting amyloid fibrils before it is degraded

Adult↗
PubMed2000

Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin.

Patients with familial amyloid polyneuropathy (FAP) are now cured by liver transplantation, but cardiac amyloidosis would further progress even after liver transplantation in some patients. To clarify the pathological mechanism of the progress of cardiac amyloidosis in FAP, we investigated cardiac tissues obtained from 6 FAP patients with 3 different types of TTR mutations. One of them had undergone liver transplantation and one year later died of cardiac amyloidosis. We determined clinical severity of cardiac involvement of those patients and characterized amyloid fibril proteins depositing in their cardiac muscles by immunohistochemistry, mass spectrometry and isoelectric focusing. All the patients had cardiac dysfunction and increased cardiac weight. Diffuse deposition of TTR-related amyloid was seen in their myocardium on microscopic examination. Amyloid fibrils of the heart were composed of wild-type TTR as well as variant TTR at a ratio of about 1:1 in 5 patients without liver transplantation. In the patient with a transplanted liver, about 80% of the cardiac amyloid consisted of wild-type TTR. Wild-type TTR contributes greatly to the development of amyloid deposition in the heart of FAP patients regardless of the types of TTR mutations.

Adult↗
PubMed2000

Molecular interactions between presenilin and calpain: inhibition of m-calpain protease activity by presenilin-1, 2 and cleavage of presenilin-1 by m-, mu-calpain.

Several mutations of presenilin (PS)-1, 2 result in early onset Alzheimer disease. Using the yeast two-hybrid system, the interaction between PS2 loop domain and the C-terminal region of mu-calpain was previously identified. Calpain is a calcium dependent-protease and there are two isoforms, m-calpain and mu-calpain, which differ in the calcium concentration required for activation. m-Calpain needs about 10(-3) M calcium ions, whereas mu-calpain about 10(-5) M. When PS and calpain were separately expressed in COS cells by cDNA transfection and then combined in vitro, or both were co-transfected to be co-expressed in vivo in COS cells, PS1 and PS2 reduced the casein proteolysis activity of m-calpain but not that of mu-calpain. Some of the PS mutations related to Alzheimer disease decreased this inhibitory activity. On the other hand, PS1 was cleaved by m-calpain and mu-calpain at a different site from those already reported (constitutive cleavage or alternative cleavage). These results suggest a regulatory function of presenilin on the calpain system.

Animals↗
PubMed1999

Presenilin-1 exists in the axoplasm fraction in the brains of aged Down's syndrome subjects and non-demented individuals.

Missense mutations in the presenilin-1 (PS-1) gene are known to be responsible for early-onset familial Alzheimer's disease (AD). The normal physiological functions of PS-1 are still incompletely understood, although data on the intracellular localization of PS-1 are accumulating, indicating that it exists mainly in endoplasmic reticulum and Golgi compartments. To investigate the localization and functions of PS-1 in the human brain, we separated axoplasm fractions from the cerebral white matter of Down's syndrome (DS) subjects with AD pathology and non-demented individuals using the axonal flotation method, and analyzed them immunocytochemically. All axoplasm fractions contained the 28-34 kDa amino-terminal fragment and the 18 kDa carboxy-terminal fragment of PS-1, although there was no specific abnormality of this protein in the DS brains with AD pathology. This finding indicates that there is intracellular trafficking of PS-1 through the axons in the human brain, and thus provides new information about the physiology of PS-1.

Adult↗
PubMed1998

A selective transthyretin-adsorption column for the treatment of patients with familial amyloid polyneuropathy.

A transthyretin (TTR)-adsorption column has been developed for the removal of variant TTR from the plasma of patients with familial amyloid polyneuropathy (FAP). The adsorbent is an ion-exchange resin made of porous beads of polyvinyl alcohol gel covalently bound with dimethylaminoethanol. This column was used for three patients with type I FAP. It reduced the concentrations of both normal and variant TTR in the plasma to about half of their pre-adsorption levels. Except for thyroxine, retinol-binding protein and IgM, other proteins in serum were not significantly decreased and there were no adverse effects in long term clinical usage of this TTR-adsorption column. In this trial, we did not obtain concrete evidence that TTR-adsorption therapy can stop or delay the progression of the disease in a FAP patient. However, if we are able to apply this technique more frequently and effectively, TTR-adsorption therapy using our column might be useful for the treatment of FAP patients.

Adsorption↗
PubMed1998

V-domain deposition of lambda Bence Jones protein in the renal tubular epithelial cells in a patient with the adult Fanconi syndrome with myeloma.

An extracted Bence Jones lambda protein from a Japanese patient with myeloma-associated Fanconi syndrome was found to contain 5 components, including the dimer and the monomer of the entire light-chain, the dimer and the monomer of the constant domain, and monomer of the variable domain. The entire amino acid sequence of this lambda chain was completed. The protein, containing 5 components, was injected intraperitoneally in C3H mice, 20 mg for 13 days and 200 mg for 3 days. Both groups of C3H mice showed a renal proximal tubular deposition of variable domain fragment of the Bence Jones protein by immunoperoxidase staining. Other control Bence Jones proteins of the lambda type and serum albumin were negative in terms of deposition in the epithelial tubular cells. It is also shown that the proximal tubules of the biopsied kidney from the patient had a deposition of variable domain fragment of Bence Jones protein. Thus, the myeloma-associated Fanconi syndrome could be included in the spectrum of light-chain associated disease or monoclonal Ig deposition disease. This is the first case of lambda type Bence Jones protein with a complete amino acid sequence analysis found in Fanconi syndrome with myeloma, demonstrating the deposition of the variable domain in the proximal tubules of the kidney.

Amino Acid Sequence↗
PubMed1997

Proteolytic processing of presenilin-1 (PS-1) is not associated with Alzheimer's disease with or without PS-1 mutations.

Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.

Alzheimer Disease↗
PubMed1996

The amino-terminally truncated forms of amyloid beta-protein in brain macrophages in the ischemic lesions of Alzheimer's disease patients.

We have investigated the cerebral cortex of Alzheimer's disease in which small infarcts are found on postmortem neuropathological examination. In areas that have been subjected to recent ischemia, immunohistochemical staining for amyloid beta-protein (A beta) is much less intense than in the non-ischemic surround. However, the infiltrating brain macrophages contain granules immunopositive for C-terminal fragments of A beta. The immunohistochemical profile indicates that A beta in these granules lacks epitopes in the N-terminal fragments. These data suggest that appropriately stimulated macrophages can phagocytose A beta deposits and that digestion of the N-terminal region is an early consequence of this phagocytosis.

Aged↗
PubMed1996

Abnormal gel-electrophoretic behavior of presenilin 1 and it's fragment.

Presenilin 1 (PS-1) is the main causal gene of familial Alzheimer's disease. In this report, we describe the abnormal behavior of PS-1 in gel electrophoresis in the presence of SDS. Freshly in vitro synthesized PS-1 was identified as a single molecule with the molecular size of 43,000 on SDS gels but was found to disappear after incubation at 37 degrees C for 24 hr due to the formation of aggregates. Intermediate aggregates with M(r) 74,000 and 100,000 were formed before the final aggregate which was retained at the top of the gel. Thus the amount of 43,000-protein species of PS-1 was found to decrease on gels with a concomitant increase in the amount of 74,000/100,000 proteins. Similar abnormality was seen in PS-1 expressed in COS cells transfected with PS-1 cDNA. Moreover, cellular PS-1 was strongly suggested to be cleaved into the fragments with M(r) approximately 20,000 in COS and CHO cells. Fragmentation of cellular PS-1 was not affected by the missense point mutation of Ala260Val on PS-1 which was identified in a pedigree with familial Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Amyloid beta protein and its 3-kDa fragment are present in the axoplasm fraction of the white matter in human brain.

Production of the soluble amyloid beta-protein (A beta) precedes abnormal accumulation of A beta amyloid in the brains of subjects with Alzheimer's disease. To determine the cellular source and generating mechanisms of soluble A beta in the human brain, we separated an axoplasm fraction from the cerebral white matter and analyzed it. The axoplasm fraction contained secretory isoforms of beta-amyloid precursor protein (APP) and 11.5 kDa A beta-bearing carboxyl-terminal fragments (CTFs) of APP. Furthermore, soluble 4 kDa A beta and 3 kDa fragments of A beta (p3) were obtained from the axoplasm fraction. These results suggest that amyloidogenic 4 kDa A beta is intracellularly produced in cerebral neurons and carried through the axons in human brain.

Aged↗
PubMed1996

Granules in glial cells of patients with Alzheimer's disease are immunopositive for C-terminal sequences of beta-amyloid protein.

Granular structures that are recognized by antibodies specific for the C-terminal but not the N-terminal sequences of the beta-amyloid protein (A beta) fragments are present in a subset of microglia and astrocytes in Alzheimer brain tissue. The immunohistochemical profile indicates that the A beta in these granules is truncated between the residues 17 and 31 and terminates at the residue 42 or 43. Such granule-containing glia occur only in brain areas with the heavy A beta deposits. Whether the intraglial A beta fragments accumulate as a result of phagocytosis of extracellular A beta or are formed intracellularly by glial cells from amyloid precursor protein (APP) remains unknown.

Aged↗
PubMed1996

No association between apolipoprotein E epsilon4 allele and the age of onset in type I familial amyloid polyneuropathy.

It has been shown that the Apolipoprotein E (ApoE) epsilon4 allele increases the risk of developing Alzheimer's disease (AD) and lowers the age of its onset. ApoE has also been suggested to be a common facilitating factor in the different types of amyloidoses. However, the association of ApoE epsilon4 with the onset of disease in various types of amyloidoses has not been extensively investigated. Type I familial amyloid polyneuropathy (FAP) is one form of systemic amyloidosis in which ApoE co-localizes with amyloid deposits. We examined 54 patients with type I FAP and found that there was no significant effect of either ApoE epsilon2 or epsilon4 allele on the age at onset. Our results suggest that ApoE4 is not a facilitating factor in the development of FAP, transthyretin amyloidosis.

Age of Onset↗
PubMed1995

The immunoreactive profile at the N-terminal region of A beta 1-39/40 but not A beta 1-42 changes with transition from monomer/dimer to further peptide aggregates.

Using site-specific antibodies, we assessed the effect of aggregation of various length forms of A beta on the immunoreactive profile of the peptides. All of the antibodies tested reacted with monomeric/dimeric forms of A beta 1-42 and its further aggregates. However, antibodies directed against the 1-24 region of A beta reacted weakly or not at all with A beta 1-39/40 monomers or dimers, but immunoreactivity was enhanced substantially following peptide incubation and aggregation. These results suggest that the conformation of the N-terminal region of monomeric and dimeric A beta 1-39/40 is different from that of aggregated forms, whereas the longer A beta 1-42 does not significantly change its N-terminal conformation during beta-sheet fibril formation. These immunochemical results are consistent with previous structural data, and help to explain the differential effects of A beta 1-39/40 and 1-42 on fibril formation in brain.

Blotting, Western↗