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Keiichi Higuchi

Publications and source records attributed to Keiichi Higuchi.

27 records · Page 2Linked to original sources
PubMed2003

Polymorphisms of mouse apolipoprotein A-II: seven alleles found among 41 inbred strains of mice.

In mice, apolipoprotein A-II (apoA-II) associates to form amyloid fibrils in an age-associated manner. We determined the complete nucleotide sequences of the apoA-II gene (Apoa2) cDNA in 41 inbred strains of mice including Mus musculus domesticus (laboratory mouse), Mus musculus castaneus, Mus musculus molossinus, Mus musculus musculus and Mus spretus. Among these strains we identified 7 alleles (Apoa2a1, Apoa2a2, Apoa2b, Apoa2c, Apoa2d, Apoa2e and Apoa2f). Polymorphisms of nucleotides at 15 positions were detected and amino acid substitutions were found at 8 positions. Apoa2a1 was found in all mouse subspecies, but Apoa2b and Apoa2c were found only in Mus musculus domesticus. Two strains of Mus spretus have the unique alleles Apoa2e and Apoa2f which resemble Apoa2c. We confirmed that VICS in which we found severe amyloidosis here and other amyloidoneic strains in published reports have Apoa2c allele. We determined the plasma concentrations of total and HDL cholesterol in the strains of Mus musculus domesticus with the Apoa2a1, Apoa2b and Apoa2c alleles. Significantly higher concentrations of plasma cholesterol were observed in mouse strains with the Apoa2b allele. These findings provide fundamental data on mouse Apoa2 alleles. Furthermore, differences in these alleles likely have considerable influence on traits related to amyloidosis and lipid metabolism.

Alleles↗
PubMed2003

A new beige mutant rat ACI/N-Lystbg-Kyo.

A new beige-like coat color mutant was identified in the ACI/N rat colony. Other features characteristic of beige mutants, such as giant granule cells in various tissues, and prolonged bleeding time were also observed. The genetic complementation test, mating beige-like mutant with the authentic beige mutant rat, DA/Ham-Lystbg, revealed that the mutant gene is allelic to Lystbg. The new beige mutant allele was denoted Lystbg-Kyo. Molecular genetic analysis revealed deletion of exons 28, 29, and 30 of the Lyst gene owing to recombination between L1 elements in the mutant rats. Although the deletion was similar to that identified in DA/Ham-Lystbg rats, the putative deletion break points in L1 elements were different in the two strains. Further characterization of the ACI/N-Lystbg-Kyo rats should make it useful as an animal model for human Chediak-Higashi syndrome.

Alleles↗
PubMed2002

Induction of protein conformational change in mouse senile amyloidosis.

Aggregated amyloid fibrils can induce further polymerization of precursor proteins in vitro, thus providing a possible basis for propagation or transmission in the pathogenesis of amyloidoses. Previously, we postulated that the transmission of amyloid fibrils induces conformational changes of endogenous amyloid protein in mouse senile amyloidosis (Xing, Y., Nakamura, A., Chiba, T., Kogishi, K., Matsushita, T., Fu, L., Guo Z., Hosokawa, M., Mori, M., and Higuchi, K. (2001) Lab. Invest. 81, 493-499). To further characterize this transmissibility, we injected amyloid fibrils (AApoAII(C)) of amyloidogenic C type apolipoprotein A-II (APOAIIC) intravenously into 2-month-old SAMR1 mice, which have B type apolipoprotein A-II (APOAIIB), and develop few if any amyloid deposits spontaneously. 10 months after amyloid injection, deposits were detected in the tongue, stomach, intestine, lungs, heart, liver, and kidneys. The intensity of deposition increased thereafter, whereas no amyloid was detected in distilled water-injected SAMR1 mice, even after 20 months. The deposited amyloid was composed of endogenous APOAIIB with a different amyloid fibril conformation. The injection of these amyloid fibrils of APOAIIB (AApoAII(B)) induced earlier and more severe amyloidosis in SAMR1 mice than the injection of AApoAII(C) amyloid fibrils. Thus, AApoAII(C) from amyloidogenic mice could induce a conformational change of less amyloidogenic APOAIIB to a different amyloid fibril structure, which could also induce amyloidosis in the less amyloidogenic strain. These results provide important insights into the pathogenesis of amyloid diseases.

Amyloid↗
PubMed2002

Deterioration in learning and memory of inferential tasks for evaluation of transitivity and symmetry in aged SAMP8 mice.

This study examined age-dependent deficits in the learning and memory of inferential tasks, using an established senescence-accelerated mouse model in age-related brain dysfunction (SAMP8) and its genetically related inbred strain (SAMR1). The mice learned two sets of nonspatial odor-odor pairs by association learning successively (i.e., A-->B, X-->Y, then B-->C, Y-->Z). They were tested in transitive inference (i.e., A-->C, X-->Z) and symmetrical inference (i.e., C-->B, Z-->Y). In the probe test of A-->C, X-->Z transitive inference, 1-month-old SAMP8 and control SAMR1 at the same age significantly chose the alternative based on transitive inference, but 4- and 7-month-old SAMP8 performed at a random chance level, in comparison with unambiguous inference by control SAMR1 at the same ages. During the test of C-->B, Z-->Y symmetrical inference, SAMP8 at 1 month of age made errors as frequently as control SAMR1 at the same age, but SAMP8 at 4 and 7 months of age made more errors than SAMR1 at the same ages. At 4 and 7 months of age, SAMP8 made more errors than 1-month-old SAMP8. Control SAMR1 did not show such an age-related deficient. These results indicate that SAMP8 mice have age-related learning and memory deficits in the ability to perform inferential tasks. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in old SAMP8 mice during the performance of inferential tasks mediated by declarative memory.

Aging↗
PubMed2002

A congenic mouse and candidate gene at the Chromosome 13 locus regulating bone density.

Previously, we identified two significant quantitative trait loci (QTLs) specifying the peak relative bone mass (bone mass corrected for bone size) on chromosomes (Chrs) 11 and 13 by interval mapping in two mouse strains, SAMP2 and SAMP6. The latter strain is an established murine model of senile osteoporosis and exhibits a significantly lower peak relative bone mass than SAMP2 mice. We recently designated the Chr 13 locus as Pbd2 (Peak bone density 2) and constructed a congenic strain, P6.P2-Pbd2(b), which carried a single genomic interval from the Chr 13 of SAMP2 on a SAMP6-derived osteoporotic background. In this study, we have constructed a congenic strain, P2.P6-Pbd2(a), carrying a SAMP6-derived susceptible interval on a SAMP2-derived resistance background. This congenic strain had a lower bone density than the background strain, SAMP2, based on three measurement methods, each utilizing a different principle for evaluating bone density: MD, DXA, and pQCT. Next, a candidate gene approach was used to find polymorphisms of Bmp6 (bone morphogenetic protein 6). The CAG trinucleotide repeat numbers in exon 1 of this gene differ among SAM strains. We found an association of CAG repeat length with relative peak bone mass in mice.

Animals↗
PubMed2002

Amyloid fibril proteins.

Amyloidosis refers to a group of protein folding diseases. Various innocuous and soluble proteins in physiological conditions polymerize to insoluble amyloid fibrils in several serious diseases, including Alzheimer's disease (AD) and prion diseases. In addition, senile amyloidosis is a form of amyloidosis in which the incidence and severity of amyloid deposition increases with age without any apparent predisposing conditions and it was thought that the amyloidosis was related to some physiological changes which accompany ageing. Although the etiology and pathogenesis of amyloid disease are not fully understood, drastic structural changes of the amyloid proteins from the normal forms to the unique beta-sheet fibrils is the most important event in amyloid diseases. The present article introduces the three amyloid diseases, AD, prion diseases and mouse senile amyloidosis in which Abeta, PrP(Sc) and AApoAII amyloid fibrils deposit respectively. We discuss the nucleation dependent polymerization model as a model that explains the kinetics of fibrillization of these amyloid proteins. Exogenous amyloid fibrils may act as templates (nuclei) and change the conformation of endogenous amyloid protein to polymerize into amyloid fibrils. This hypothesis makes the boundary between transmissible and non-transmissible amyloidosis ambiguous and proposes the common pathogenesis for them.

Aging↗
PubMed2002

Glial fibrillary acidic protein is greatly modified by oxidative stress in aceruloplasminemia brain.

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin (Cp) gene. The neuropathological hallmark of this disease is intracellular iron overload, which is thought to lead to neuronal cell death through increased oxidative stress. We evaluated and characterized protein oxidation in the brain of a patient with this disease. The protein carbonyl content in the cerebral cortex of the patient was elevated compared to controls. Furthermore, peptide mass fingerprinting and partial amino acid sequencing identified glial fibrillary acidic protein (GFAP) as the major carbonylated protein in the cerebral cortex of the patient. In conjunction with the facts that Cp mainly localizes to astrocytes in the central nervous system and that astrocytes are loaded with much more iron than neurons in the cerebral cortex, our findings indicate that Cp deficiency may primarily damage astrocytes. We speculate that the dysfunction of astrocytes may be causatively related to neuronal cell loss in aceruloplasminemia.

Brain↗
PubMed2002

Predominant apolipoprotein J exists as lipid-poor mixtures in cerebrospinal fluid.

Apolipoprotein (apo) J, abundant in cerebrospinal fluid (CSF), is known to play a role in the pathogenesis of Alzheimer's disease (AD); however, the mechanism remains obscure. To characterize the apoJ-containing lipoproteins in CSF, we compared the distribution of apoJ in CSF lipoprotein partides with those of apoE and apoAI. CSF lipoproteins (fractionated by ultracentrifugation, gel-filtration chromatography, and agarose-gel electrophoresis) were characterized by immunoblot analysis using anti-apoJ, anti-apoE, and anti-apoAI antibodies. Immunoprecipitation and immunoabsorption were used to clarify the combinations in which these apolipoproteins exist. All of the apoJ in CSF was in the fraction with density of > or = 1.250 g/ml after ultracentrifugation; relatively little apoE and apoAI was in that fraction. In gel-filtration chromatography, the main peak of apoJ-containing lipoprotein particles was clearly distinguishable from those of apoE- and apoAI-containing lipoproteins. Immunoabsorption and agarose-gel electrophoresis indicated that the dominant apoJ-containing lipoprotein partides did not contain apoE. These findings indicate that a significant fraction of the apoJ present in CSF does not co-exist with apoE or apoAI within the same particles. Immunoprecipitation revealed two types of particles: one that contains no apoAl but apoE and another that contains no apoE but apoAI. These results show that several subfractions of lipoprotein particles exist in CSF, differing from each other in their combinations of apoE, apoJ, and apoAI. We concluded that there are at least 9 forms or combinations (including free apolipoproteins) of apoJ, apoE, and apoAl in the CSF.

Apolipoprotein A-I↗