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Makoto Higuchi

Publications and source records attributed to Makoto Higuchi.

At least 37 records · Page 2Linked to original sources
PubMed2005

Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice.

Calpain has been implicated in excitotoxic neurode-generation, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainate-evoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondria-derived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.

Animals↗
PubMed2005

Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease.

Amyloid beta peptide (A beta) has been implicated in Alzheimer's disease (AD) as an initiator of the pathological cascades. Several lines of compelling evidence have supported major roles of A beta-degrading enzyme neprilysin in the pathogenesis of sporadic AD. Here, we have shown a substantial reduction of cerebrospinal fluid (CSF) neprilysin activity (CSF-NEP) in patients with AD-converted mild cognitive impairment and early AD as compared with age-matched control subjects. The altered CSF-NEP likely reflects changes in neuronal neprilysin, since transfer of neprilysin from brain tissue into CSF was demonstrated by injecting neprilysin-carrying viral vector into the brains of neprilysin-deficient mice. Interestingly, CSF-NEP showed an elevation with the progression of AD. Along with a close association of CSF-NEP with CSF tau proteins, this finding suggests that presynaptically located neprilysin can be released into CSF as a consequence of synaptic disruption. The impact of neuronal damages on CSF-NEP was further demonstrated by a prominent increase of CSF-NEP in rats exhibiting kainate-induced neurodegeneration. Our results unequivocally indicate significance of CSF-NEP as a biochemical indicator to pursue a pathological process that involves decreased neprilysin activity and A beta-induced synaptic toxicity, and the support the potential benefits of neprilysin up-regulation in ameliorating neuropathology in prodromal and early AD.

Aged↗
PubMed2005

Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model.

Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only one T44 tau Tg mouse subjected to mrTBI remain to be elucidated.

Animals↗
PubMed2005

Immunohistochemical detection of immunoglobulins and complements in formaldehyde-fixed and paraffin-embedded renal biopsy tissues; an adjunct for diagnosis of glomerulonephritis.

BACKGROUND: The present study was undertaken to demonstrate the deposition of immunoglobulins or complements in formaldehyde-fixed and paraffin-embedded renal biopsy tissues through the unmasking of antigens with microwave treatment plus protease digestion or trypsin digestion. METHODS: Biopsy samples from patients with IgA nephritis (n = 7), lupus nephritis (7), membranous nephropathy (7) and mesangiocapillary glomerulonephritis (3) were used. Antigen unmasking was performed with (i) microwave treatment plus protease digestion for 10, 30 or 60 min, or (ii) digestion with 0.25% trypsin for 60 or 120 min. RESULTS: Microwave treatment plus protease digestion for 30 or 60 min and trypsin digestion for 120 min provided good results for the unmasking of immunoglobulins in glomeruli with structural preservation. The IgA deposits in IgA nephritis and IgG deposits in lupus nephritis and membranous nephropathy were clearly revealed in more than 80% of cases by both pretreatments. Microwave treatment plus protease digestion for 30 min revealed the deposition of C3 in all cases of mesangiocapillary glomerulonephritis and lupus nephritis and was superior to trypsin digestion. Characteristic patterns of C3 deposition were observed for these forms of glomerulonephritis, although C3 deposits in membranous nephropathy were detected in only 50% of cases. It was not possible to unmask all of the antigens in the glomeruli, especially those with weak immunofluorescence. CONCLUSION: Microwave treatment plus protease digestion is effective for the unmasking of antigens in paraffin sections and as useful for the diagnosis of immune-mediated glomerulonephritis as trypsin digestion.

Biopsy↗
PubMed2005

Epstein-Barr virus-related primary central nervous system lymphoma after cadaveric renal transplantation improved by treatment with high-dose methotrexate followed by irradiation.

A 57-year-old man was admitted to hospital because of motor aphasia on 16 September 2000. He had an approximate 2-year history of haemodialysis treatment, since April 1997, and had received a cadaveric renal transplantation in July 1999. Computed tomography and magnetic resonance imaging (MRI) revealed a mass with ringed enhancement in the left temporal-parietal lobe. Primary central nervous system (CNS) lymphoma (diffuse large B cell type) was diagnosed based on an open brain tumour biopsy. Epstein-Barr virus early RNA (EBER) in situ hybridization showed positive signals in the nuclei of the CNS lymphoma cells. A dose reduction of immunosuppressant and three series of high-dose methotrexate (MTX) therapy with leucovorine rescue followed by irradiation (whole brain irradiation, 30 Gy; partial brain tumour irradiation, 20 Gy) were carried out for his primary CNS lymphoma. The patient is currently in good condition (September 2004) with no enlargement of the lymphoma, as examined by MRI every 3 months, and preserved renal function.

Aged↗
PubMed2005

A case of drug-induced hypersensitivity syndrome with multiple organ involvement treated with plasma exchange.

A 53-year-old male patient began treatment for systemic exanthema with diaphenylsulfone (DHS) on 21 November 2002. On 18 December 2002, the patient developed a fever and additional systemic erythematous exanthema. Systemic lymphadenopathy, hepatosplenomegaly, leukocytosis (in particular, an increase in the number of atypical lymphocytes) and liver dysfunction followed. After cessation of the DHS treatment on 25 December 2002, acute renal failure occurred and the patient was transferred to Shinshu University Hospital on 4 January 2003. The patient was diagnosed with drug-induced hypersensitivity syndrome (DIHS). Steroid pulse therapy (methylprednisolone 1000 mg/day for 3 days) was given, followed by 60 mg/day of prednisolone. The patient's renal functions recovered and he was taken off hemodialysis therapy. However, the patient relapsed twice despite two sessions of steroid pulse therapy and an increase in the dose of prednisolone to 100 mg/day. Plasma exchange (PE) was carried out to reduce the activity of the disease. With a total of four plasma exchanges, we were able to reduce the dose of prednisolone from 100 mg/day to 60 mg/day without relapse. There were no adverse effects from the plasma exchanges. Plasma exchange should be considered in the treatment with corticosteroid-resistant DIHS with multiple organ lesions.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy.

Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenic tau gene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds. RW but not hWT tau Tg mice developed an age-dependent accumulation of insoluble filamentous tau aggregates in neuronal perikarya of the cerebral cortex, hippocampus, cerebellum, and spinal cord. Significantly, CNS axons in RW mice contained reduced levels of tau when compared with hWT mice, and this was linked to retarded axonal transport and increased accumulation of an insoluble pool of RW but not hWT tau. Furthermore, RW but not hWT mice demonstrated neurodegeneration and a reduced lifespan. These data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport. This altered tau function caused by the RW mutation leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.

Aging↗
PubMed2004

Olfactory dysfunction occurs in transgenic mice overexpressing human tau protein.

Disorders of olfaction are among the first clinical signs of neurodegenerative diseases such as Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD). In this study, we employed an odor habituation paradigm to evaluate the olfactory function of T alpha 1-3RT transgenic mice that overexpress tau, a key pathogenic protein in AD, and compared such function to that of wild-type controls who do not overexpress this protein. The T alpha 1-3RT mice, but not the controls, exhibited responses indicative of decreased olfactory function. These data lend support to the notion that tau may be involved in the pathogenesis of the olfactory dysfunction of some neurodegenerative diseases. Future studies need to similarly assess other pathogenic markers, as well as their distribution within various sectors of the brain, to determine the specificity of this phenomenon.

Animals↗
PubMed2004

Fluoro-substituted and 13C-labeled styrylbenzene derivatives for detecting brain amyloid plaques.

Two styrylbenzene derivatives, (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB) and (E,E)-1-bromo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene-alpha,alpha'-(13)C(2) ([(13)C]BSB), were synthesized for use as a histochemical stain to detect amyloid plaques of Alzheimer's disease (AD) brain sections. An analysis of fluorescence spectra demonstrated that FSB shows approximately twofold fluorescence intensity relative to the conventional styrylbenzene derivative, (E,E)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB). Moreover, FSB was found to stain amyloid plaques and neurofibrillary tangles of AD brains with greater fluorescence intensity and a lower level of background signals compared to BSB. These finding indicate that FSB can be an excellent fluorescent compound to label human amyloid lesions with high sensitivity and specificity. Because of the possession of a nuclide with a quantized angular momentum, both FSB and [(13)C]BSB are also potential contrast agents for magnetic resonance imaging to locate AD pathologies in vivo.

Alzheimer Disease↗
PubMed2003

Initiation and synergistic fibrillization of tau and alpha-synuclein.

Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.

Amyloid↗
PubMed2003

POEMS syndrome caused refractory ascites in a polycystic disease patient undergoing hemodialysis.

A 60-year-old man with polycystic disease (PCD) undergoing hemodialysis was admitted to our hospital because of refractory ascites in September 2000. He had been diagnosed with probable chronic inflammatory demyelinating polyradiculopathy 6 months before admission. Though the ascites was bloody and exudative, the cytology was normal and cultures of bacteria and acid-fast bacillus were both negative. Hepatic venous outflow obstruction was excluded by several radiological examinations. Because of the presence of polyneuropathy, organomegaly, endocrine abnormality, M-protein, plasma cell dyscrasia, and skin lesions, POEMS, syndrome was diagnosed; this had caused the refractory ascites. Initial prednisolone therapy was effective for the refractory ascites, but it was not effective in preventing recurrence. He died due to cachexia in December 2000. This is a very rare case of the presence of both PCD and POEMS syndrome in a patient.

Antibodies↗
PubMed2003

Clinical significance of SEN virus infection in patients on maintenance haemodialysis.

BACKGROUND: The SEN virus (SENV) has been identified as a putative new hepatitis virus. This study was conducted to clarify the clinical significance of SENV infection in patients on haemodialysis. METHODS: A total of 189 patients on maintenance haemodialysis and 60 healthy controls were enrolled. Of the 189 patients, 154 were followed up for 2 years. SENV DNA (genotypes D and H) was measured by means of polymerase chain reaction. RESULTS: SENV infection was significantly (P=0.012) more prevalent in patients on haemodialysis (38%) than in controls (22%). SENV infection was not associated with the amount of transfusion or duration of haemodialysis, while hepatitis C virus (HCV) infection was significantly associated with both of these factors. Elevation of alanine aminotransferase was significantly associated with HCV, but not with SENV viraemia. Of the 154 patients who were followed up, 63 (41%) remained negative, 34 (22%) gained positivity, 28 (18%) lost it and 29 (19%) remained positive for SENV infection. Episodes of alanine aminotransferase elevation were recorded for 3% of the patients who incurred SENV infection and this rate was similar to that observed in patients who were continuously negative for SENV infection (5%). CONCLUSIONS: SENV infection was common in patients on haemodialysis. No evidence was obtained that suggested involvement of the hepatitis virus in the pathogenicity of SENV.

Adult↗
PubMed2003

Expression of hepatocyte growth factor is induced by the interaction between human mesangial cells and monocytes.

BACKGROUND: In pathological states various cytokines are produced by mesangial cells (MC) and contribute to disease progression. It is likely that interactions between monocytes and MC partially regulate these cytokines, including hepatocyte growth factor (HGF). Because HGF might have a potent therapeutic effect on the kidney, it is believed to play a critical role in the pathogenesis and development of glomerulonephritis. However, there is little knowledge about HGF production by MC or infiltrated monocytes in glomerulonephritis. METHODS: To investigate HGF expression in pathological states, we cultured human MC (hMC) with a human monocytoid cell line and assessed HGF mRNA expression and protein production. Next, we performed immunohistochemical staining to explore which types of cell in the co-culture system expressed HGF. Because several humoral factors that can induce HGF production have been reported, we also performed noncontact co-culture to explore the contribution of humoral factors. RESULTS: The HGF concentration of the co-culture system showed a time-dependent increase, and was fourfold greater than that of hMC alone. Expression of HGF mRNA was also increased. Both THP-1 cells and hMC in the co-culture demonstrated staining of HGF. The HGF concentration in the noncontact co-cultures was smaller than in the ordinary ones, but was greater than hMC alone. CONCLUSION: Direct cell-to-cell interaction between hMC and monocytes induced HGF production of both types of cells, indicating that local HGF production induced by cell-to-cell interaction plays an important role in the pathogenesis of glomerulonephritis. While direct cell-to-cell contact was important for HGF production, it is considered that some humoral factors might contribute.

Cell Communication↗
PubMed2002

Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration.

Frontotemporal dementias (FTDs), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), are neurodegenerative tauopathies characterized by widespread CNS neuronal and glial tau pathologies, but there are no tau transgenic (Tg) mice that model neurodegeneration with glia tau lesions. Thus, we generated Tg mice overexpressing human tau in neurons and glia. No neuronal tau aggregates were detected, but old mice developed Thioflavin S- and Gallyas-positive glial tau pathology resembling CBD astrocytic plaques. Tau-immunoreactive and Gallyas-positive oligodendroglial coiled bodies (similar to CBD and PSP), glial degeneration, and motor deficits were associated with age-dependent accumulations of insoluble hyperphosphorylated human tau and tau immunopositive filaments in degenerating glial cells. Thus, tau-positive glial lesions similar to human FTDs occur in these Tg mice, and these pathologies are linked to glial and axonal degeneration.

Aging↗
PubMed2002

Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam.

Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.

Amyotrophic Lateral Sclerosis↗