PINK1, a gene product of PARK6, accumulates in alpha-synucleinopathy brains.
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Brain Diseases↗
Biomedical subjects
Mikio Shoji
Publications and source records attributed to Mikio Shoji.
Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.
The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.
Aged↗
Enhanced accumulation of tau in doubly transgenic mice expressing mutant betaAPP and presenilin-1.
Abeta amyloidosis and tauopathy are characteristic changes in the brain of Alzheimer's disease. Although much evidence suggests that Abeta deposit is a critical initiation factor, the pathological pathway between Abeta amyloidosis and tau accumulation remains unclear. Tau accumulation was examined in the doubly transgenic mouse (APP-PS) expressing betaAPP(KM670/671NL) (Tg2576) and presenilin-1 L286V (PS-1 L286Vtg). Accelerated and enhanced Abeta amyloid deposits were detected from 8 weeks. Tau accumulation appeared at 4.5 months and markedly increased in dystrophic neurites around Abeta amyloid. Accumulated tau was phosphorylated, conformationally altered, and argyrophilic. Expression of tau and accumulation of sarkosyl-insoluble phosphorylated tau were increased in APP-PS brains compared with those of Tg2576 mice. Straight or twisted tubules mimicking paired helical filament were revealed at electron microscopic level in 16-month-old APP-PS. These findings suggest that mutant presenilin-1 accelerated Abeta-induced tauopathy and further promoted fibril formation of tau.
Alzheimer Disease↗
Distribution of inducible nitric oxide synthase and cell proliferation in rat brain after transient middle cerebral artery occlusion.
Nitric oxide (NO) can be neuroprotective or neurotoxic during cerebral ischemia, depending on the NO synthase (NOS) isoform involved. In addition to neurotoxic effect in ischemic brain, inducible NOS (iNOS) also adversely affect ischemic outcome by blocking neurogenesis. In the present study, therefore, we studied the chronological and spatial change of the distribution of iNOS and cell proliferation in subventricular zone (SVZ) after transient focal cerebral ischemia. After 90 min of transient middle cerebral artery occlusion (tMCAO), iNOS-positive cells decreased in the ischemic core at 1 to 21 days, and increased in the ipsilateral periischemic area at 1 and 3 days. 5-Bromodeoxyuridine (BrdU)-positive cells appeared in the ischemic core at 3 to 21 days, appeared in the periischemic area at 3 and 7 days, and increased in the ipsilateral SVZ at 7 days. ED-1-positive cells appeared in the ischemic core at 3 to 21 days, and some of them were double positive with BrdU or iNOS, but the majority were BrdU-negative. The present study suggests that astrocytes are born within the periischemic area at early stage after tMCAO and migrate from SVZ into periischemic area at later stage, and that time-dependent and spatial changes of iNOS expression may be involved in the proliferation and differentiation of adult neurogenesis after focal cerebral ischemia.
Animals↗
Implantation of a new porous gelatin-siloxane hybrid into a brain lesion as a potential scaffold for tissue regeneration.
For brain tissue regeneration, any scaffold for migrated or transplanted stem cells with supportive angiogenesis is important once necrotic brain tissue has formed a cavity after injury such as cerebral ischemia. In this study, a new porous gelatin-siloxane hybrid derived from the integration of gelatin and 3-(glycidoxypropyl) trimethoxysilane was implanted as a three-dimensional scaffold into a defect of the cerebral cortex. The porous hybrid implanted into the lesion remained at the same site for 60 days, kept integrity of the brain shape, and attached well to the surrounding brain tissues. Marginal cavities of the scaffolds were occupied by newly formed tissue in the brain, where newly produced vascular endothelial, astroglial, and microglial cells were found with bromodeoxyuridine double positivity, and the numbers of those cells were dose-dependently increased with the addition of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Extension of dendrites was also found from the surrounding cerebral cortex to the newly formed tissue, especially with the addition of bFGF and EGF. The present study showed that a new porous gelatin-siloxane hybrid had biocompatibility after implantation into a lesion of the central nervous system, and thus provided a potential scaffold for cell migration, angiogenesis and dendrite elongation with dose-dependent effects of additive bFGF and EGF.
Animals↗
Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene.
We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.
Amyotrophic Lateral Sclerosis↗
Superoxide dismutase-encoding gene of the obligate anaerobe Porphyromonas gingivalis is regulated by the redox-sensing transcription activator OxyR.
Inspection of the genomic DNA sequence of the oral anaerobe Porphyromonas gingivalis reveals that the micro-organism possesses the peroxide-sensing transcription activator OxyR, but not the superoxide-sensing transcription factor SoxR. Investigatation of oxidative-stress-responsive proteins in P. gingivalis by two-dimensional gel electrophoresis showed that two proteins were predominantly upregulated in oxidative conditions. In a P. gingivalis oxyR mutant these two proteins were not induced by treatment with hydrogen peroxide under aerobic conditions. By N-terminal amino acid sequencing, the two proteins were found to be superoxide dismutase and alkyl hydroperoxide reductase, encoded by sod and ahpC, respectively. Northern blot and lacZ fusion analyses revealed that P. gingivalis sod and ahpC were positively regulated by OxyR. Primer extension analysis located the promoter regions of sod and ahpC, and putative -35 boxes of these promoters were found immediately adjacent to their putative OxyR-binding sequences. Moreover, the promoter regions of sod and ahpC had the ability to bind P. gingivalis OxyR protein. These results demonstrate that P. gingivalis sod is one of the OxyR regulons, suggesting that OxyR functions as an intracellular redox sensor rather than a peroxide sensor in this organism. A sod gene of Bacteroides fragilis, which is taxonomically related to P. gingivalis, is inducible by redox stresses but not controlled by its OxyR. A DNA fragment including the B. fragilis sod promoter region could bind the P. gingivalis OxyR protein; however, a putative OxyR binding sequence within the DNA fragment was 14 bases distant from a putative -35 box of its promoter.
Adaptation, Physiological↗
Porphyromonas gingivalis-induced platelet aggregation in plasma depends on Hgp44 adhesin but not Rgp proteinase.
Evidence from recent epidemiological studies suggests a link between periodontal infections and increased risk of atherosclerosis and related cardiovascular and cerebrovascular events in human subjects. One of the major pathogens of periodontitis, Porphyromonas gingivalis, has the ability to aggregate human platelets in platelet-rich plasma (PRP). Mechanism of P. gingivalis-induced platelet aggregation in PRP was investigated. Proteinase inhibitors toward Arg-gingipain (Rgp) and Lys-gingipain (Kgp) did not suppress P. gingivalis-induced platelet aggregation in PRP, whereas the Rgp inhibitor markedly inhibited P. gingivalis-induced platelet aggregation using washed platelets. Mutant analysis revealed that P. gingivalis-induced platelet aggregation in PRP depended on Rgp-, Kgp- and haemagglutinin A (HagA)-encoding genes that intragenically coded for adhesins such as Hgp44. Hgp44 adhesin on the bacterial cell surface, which was processed by Rgp and Kgp proteinases, was essential for P. gingivalis-induced platelet aggregation in PRP. P. gingivalis cell-reactive IgG in plasma, and FcgammaRIIa receptor and to a lesser extent GPIbalpha receptor on platelets were found to be a prerequisite for P. gingivalis-induced platelet aggregation in PRP. These results reveal a novel mechanism of platelet aggregation by P. gingivalis.
Adhesins, Bacterial↗
Temporal profile of neural stem cell proliferation in the subventricular zone after ischemia/hypoxia in the neonatal rat brain.
OBJECTIVES: Ischemia/hypoxia (I/H) causes severe neonatal brain injury, such as periventricular leukomaracia and hypoxic/ischemic encephalopathy. Neural stem cell research could lead to a treatment for such disorders. In order to elucidate the dynamic changes in neural stem cells in the neonatal brain after I/H, we investigated the proliferation of new cells in the subventricular zone (SVZ). METHODS: Seven-day-old Wister rats were subjected to ligation of the left carotid artery followed by 2 hours of hypoxic stress (8% O(2) and 92% N(2), at 33 degrees C). In order to elucidate the dynamic change of neural stem cells in the SVZ, single bromodeoxyuridine (BrdU; 50 mg/kg) was administered 2 hours before death 1, 7, 14 and 21 days after I/H. Immunohistochemical and immunofluorescent studies for BrdU and doublecortin (DCX) were carried out. As a control, a group of rats was subjected to sham surgery (incision of skin, but no ligation of the carotid artery) and no I/H. RESULTS: The numbers of BrdU-labeled cells in the SVZ, for both the ipsilateral side and the contralateral side of the I/H brain, were twice the level of the control at 7 days after I/H, but the numbers for both sides returned to the control level at 21 days. In the ipsilateral side of the I/H brain, the number of BrdU-labeled cells in the SVZb (lining the upper wall of lateral ventricle) was 4-fold at 7 days and 15-fold at 21 days after I/H compared with the control level. This chronological pattern is very similar to the pattern for I/H results of the posterior periventricle (pPV). DCX appeared in most BrdU-labeled cells in the SVZb and pPV. DISCUSSION: These findings indicate that I/H enhances neural stem cell proliferation in the SVZ, and some newborn cells migrate as neural precursors to the SVZb and pPV after I/H in the neonatal rat brain.
Animals↗
Molecular mechanisms of ischemic neuronal cell death--with relevance to Alzheimer's disease.
There are many similarities in molecular mechanisms of neuronal cell death observed in ischemic stroke and Alzheimer's disease. From point of organelle damage, we introduced molecular events seen in ischemic stroke, and compared the findings with that observed in Alzheimer's disease. In the brain after ischemia, transmembrane potential and ion gradient are disturbed at very early stage. Several drugs are aimed to minimize this change, some of which were effective in experimental models. Calcium blocker and glutamate antagonist were also effective for Alzheimer's disease. As for mitochondrial and endoplasmic reticulum damage, both disorders share common pathological findings such as pro-apoptotic signals activation. However, there are some molecules which are neuroprotective in Alzheimer's disease but pro-apoptotic in ischemic neurons. We need to be so careful for judging the significance of a phenomenon obtained by an experiment. Lysosome, called as suicide bag, play important roles both in the brain of ischemic stroke and Alzheimer's disease. Leak of lysosomal enzymes influence, at least partially, the fate of neurons under pathological conditions in both disorders.
Alzheimer Disease↗
Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.
Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.
Animals↗
[Alzheimer's disease as brain amyloidosis: diagnosis using cerebrospinal fluid abeta and tau].
Recent progress in the treatment for Alzheimer's disease (AD) emphasizes the need for early diagnosis of AD. It is also becoming a noteworthy issue to determine if a patient with mild cognitive impairment (MCI) has incipient AD. Three cerebrospinal fluid (CSF) biomarkers: beta-amyloid42 (Abeta42), total tau (t-tau) and phosphorylated tau (p-tau) have been evaluated in numerous scientific papers. Summary of these large-scale studies suggested that measurements of Abeta40/42 and t-tau in CSF are clinically useful for the diagnosis of AD, especially when they are combined. Studies showed that measurement of p-tau improves the early and differential diagnosis of AD. They are also useful markers to identify incipient AD in MCI cases. Early diagnosis of AD using these assays is an evidence-based biomarker that can be the basis for treatment with drugs aimed at targeting the degenerating processes of AD.
Alzheimer Disease↗
Type-specific evolution of amyloid plaque and angiopathy in APPsw mice.
To clarify how Abeta deposits start in the brain, we examined the early to late stages of senile plaques and amyloid angiopathy in APPsw mice. All types of human senile plaques were observed in the mouse brains. The premature forms of cored plaques appeared first in the cerebral cortex of mice at 7-8 months old. Then, amyloid angiopathy emerged, followed by diffuse plaques consisting of Abeta1-42. Modifications of the N-terminus of Abeta were late phase phenomena. The premature forms of cored plaques were composed of central Abeta1-40 amyloid cores, surrounding amorphous Abeta1-42 deposits, and accumulation of Abeta1-42 in some peripheral cells. These cells were incorporated in amyloid cores, and these plaques developed to large cored plaques composed of Abeta1-40 and Abeta1-42. The size and number of cored plaques were increased with age. These findings indicate different evolution paths for cored plaques and diffuse plaques, and suggest the presence of a pathway that initiates with the intracellular accumulation of Abeta1-42 and leads to the development of classic plaques in human brain tissues.
Aging↗
Prevention of spinal motor neuron death by insulin-like growth factor-1 associating with the signal transduction systems in SODG93A transgenic mice.
The role of insulin-like growth factor-1 (IGF-1) in amyotrophic lateral sclerosis (ALS) and its mechanism of action are important from both pathogenic and therapeutic points of view. The present study investigated the changes of IGF-1Rbeta and the key intracellular downstream protein insulin receptor substrate-1 (IRS-1) by using SOD1(G93A) transgenic mice with continuous intrathecal IGF-1 treatment. The number of lumbar spinal motor neurons was preserved with IGF-1 treatment in a dose-dependent manner. The numbers of immunopositive motor neurons for IGF-1Rbeta and IRS-1 were not significantly different between wild-type and Tg mice with vehicle treatment, whereas treatment of Tg mice with IGF-1 decreased the numbers of immunopositive motor neurons in a dose-dependent manner. On the other hand, the ratio of immunopositive motor neurons per total living motor neurons in vehicle-treated mice was greatly increased in Tg mice with vehicle treatment compared with wild-type mice. With IGF-1 treatment, the ratio was dramatically decreased in a dose-dependent manner. These results suggest that IGF-1 treatment prevents motor neuron loss by affecting the signal transduction system through IGF-1R and the main downstream signal, IRS-1.
Analysis of Variance↗
Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of Amyotrophic Lateral Sclerosis.
Insulin-like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with amyotrophic lateral sclerosis (ALS) when given subcutaneously. To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Taken together, the results suggest that direct administration of IGF-1 into the intrathecal space may have a therapeutic benefit for ALS.
Age Factors↗
[Diagnostic approach to dementia of the aged].
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Aged↗
The protective effect of dantrolene on ischemic neuronal cell death is associated with reduced expression of endoplasmic reticulum stress markers.
The endoplasmic reticulum (ER) plays an important role in ischemic neuronal cell death. In order to determine the effect of dantrolene, a ryanodine receptor antagonist, on ER stress response and ischemic brain injury, we investigated changes in ER stress-related molecules, that is phosphorylated form of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), phosphorylated form of eukaryotic initiation factor 2alpha (p-eIF2alpha), activating transcription factor-4 (ATF-4), and C/EBP-homologous protein (CHOP), as well as terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in the peri-ischemic area and ischemic core region of rat brain after transient middle cerebral artery occlusion (MCAO). In contrast to the cases treated with vehicle, the infarct volume and TUNEL-positive cells were significantly reduced at 24 h of reperfusion by treatment with dantrolene. The immunoreactivities for p-PERK, p-eIF2alpha, ATF-4, and CHOP were increased at the ischemic peripheral region after MCAO, which were partially inhibited by dantrolene treatment. The present results suggest that dantrolene significantly decreased infarct volume and provided neuroprotective effect on rats after transient MCAO by reducing ER stress-mediated apoptotic signal pathway activation in the ischemic area.
Activating Transcription Factor 4↗
Up-regulation of low-density lipoprotein receptor expression in the ischemic core and the peri-ischemic area after transient MCA occlusion in rats.
Low-density lipoprotein (LDL) receptor is involved in cholesterol metabolism of CNS as a receptor of apolipoprotein E (ApoE), which plays an important role in regenerative process after brain ischemia. Temporal and spatial changes of LDL receptor were investigated after 90 min of transient middle cerebral artery occlusion (MCAO) in relation to those of microtubule-associated protein 2 (MAP2) and ApoE. In the ischemic core, LDL receptor became positive at 1 d after transient MCAO, which was not double positive for MAP2 or ApoE, and disappeared in 7 and 56 d. In the peri-ischemic area, LDL receptor became observed at 7 d, which peaked at 21 d, most of which were double positive for MAP2. The number of LDL receptor and ApoE double-positive cells increased at 7 d and decreased at 21 d with the shift of LDL receptor immunoreactivity from cytoplasm at 7 d to dendrites at 21 d in the peri-ischemic area. These results suggest that LDL receptor, interacting with ApoE, is profoundly involved in lipid transport of CNS for tissue repair in the peri-ischemic area after brain ischemia.
Animals↗