Nyoka N Ruberu's scientific contributionswhile working at Tokyo Metropolitan Institute of Gerontology (Tokyo, Japan) and other institutions
- Abstract: Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy... Show More
- Abstract: A monoclonal antibody specific to apolipoprotein E 4 (apoE4) was applied immunohistochemically to archival human brain tissue. The examined 30 cases comprised four epsilon/epsilon4, 10 epsilon3/epsilon4, one epsilon2/epsilon4, 10 epsilon3/epsilon3 and five epsilon2/epsilon3 genotypes. The anti apoE4 antibody visualized senile plaques, neurofibrillary tangles and reactive astrocytes, as well as serum in the blood vessels and vascular smooth muscle cells in the cases of epsilon4. Moreover, the... Show More
- Abstract: The present report is an autopsy case of an 83 year old man with severe kyphoscoliosis and granulomatous meningitis as a late complication of iodized oil myelography. He suffered from mild cognitive impairment and died of pneumonia. At autopsy, the brain showed yellow-brown granular material on its surface, mainly in the Sylvian fissure. Microscopically, granulation tissue was seen around areas of ossification encasing the foreign material. Iodized oil apparently changed into two types of... Show More
- Abstract: Estrogen receptor alpha (ERalpha) may be implicated in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to clarify the association between ERalpha gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERalpha gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age,... Show More
- Abstract: To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging, we investigated the incidence of LBs in 1,241 consecutive autopsy cases (663 males and 578 females). LB pathology was identified histologically in sections stained with hematoxylin and eosin and with anti-ubiquitin and anti-alpha-synuclein antibodies. Cases without LBs were classified as LB stage 0 (987 cases). Cases with LBs were classified as follows: LB stage I = incidental LBs (149 cases); LB stage II =... Show More
- Abstract: We have reported that the ambient gyrus is the site with the greatest accumulation of argyrophilic grains (AGs) and that the degeneration of the ambient gyrus is responsible for dementia with grains. Here we analyzed 1,405 serial autopsy cases from 2 hospitals and detected AGs only in cases older than 56 years of age. The distribution of AGs followed a stereotypic regional pattern. Thus, we propose the following staging paradigm: stage I: AGs restricted to the ambient gyrus and its vicinity;... Show More
- Abstract: In order to clarify the significance of Lewy body (LB)-related α-synucleinopathy in aging, we investigated the incidence of LBs in 1241 consecutive autopsy cases (663 male and 578 female) from a community-based general geriatric hospital between 1995 and 2002. LB pathology was evaluated histologically in sections stained with hematoxylin and eosin and immunocytochemically with anti-ubiquitin and anti-α-synuclein antibodies. Cases without LBs were classified into LB Stage 0 (987 cases). Cases... Show More
Publications citing this author (562)
[Show abstract] [Hide abstract] ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls. In vivo striatal dopamine release was insensitive to the LRRK2 inhibitor Nov-LRRK2-11, and was elevated by the membrane dopamine transporter blocker GBR-12783. However, G2019S knock-in mice showed a blunted neurochemical and motor activation response to GBR-12783 compared to wild-type controls. Western blot and dopamine uptake analysis revealed an increase in dopamine transporter levels and activity in the striatum of 12-month-old G2019S KI mice. This phenotype correlated with a reduction in vesicular monoamine transporter 2 levels and an enhancement of vesicular dopamine uptake, which was consistent with greater resistance to reserpine-induced hypolocomotion. These changes were not observed in 3-month-old mice. Finally, Western blot analysis revealed no genotype difference in striatal levels of endogenous α-synuclein or α-synuclein bound to DOPAL (a toxic metabolite of dopamine). However, Serine129-phosphorylated α-synuclein levels were higher in 12-month-old G2019S knock-in mice. Immunohistochemistry confirmed this finding, also showing no genotype difference in 3-month-old mice. We conclude that the G2019S mutation causes progressive dysfunctions of dopamine transporters, along with Serine129-phosphorylated α-synuclein overload, at striatal dopaminergic terminals, which are not associated with dopamine homeostasis dysregulation or neuron loss but might contribute to intrinsic dopaminergic terminal vulnerability. We propose G2019S knock-in mice as a presymptomatic Parkinson’s disease model, useful to investigate the pathogenic interaction among genetics, aging, and internal or environmental factors leading to the disease.
- No significant difference between genotypes was found. We then investigated pSer129 α-syn levels (Fig. 7b, c), since this posttranslational modification of α-syn is thought to influence α-syn aggregation and is highly represented in intracellular inclusions and Lewy Bodies [1, 24, 69]. Total endogenous α-syn levels were not different between genotypes (Fig. 7b) whereas pSer129 α-syn levels were ~2-fold higher in the striatum of G2019S KI mice (Fig. 7c).
[Show abstract] [Hide abstract] ABSTRACT: In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.
- Taken together, α-syn accumulation in the hippocampus and the amygdala develops the pathology of PDD and DLB. Similarly, the α-syn accumulation therein is exhibited in part of AD, leading to cognitive declines . Moreover, neurons in the VTA/medial SNc provide the mesocortical dopamine pathway to the frontal lobe [3,38,52], and, therefore, a large part of the frontal lobe is thought to receive dopaminergic innervation in varying degree .
[Show abstract] [Hide abstract] ABSTRACT: Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer’s disease (AD) which is the most common form of dementia. AD is a tauopathy characterized by both extracellular amyloid-β plaques in addition to intracellular neurofibrillary tangles and neuropil threads containing aggregated tau protein. Accumulating evidence suggests that neuroinflammation offers a possible mechanistic link between these pathologies. Additionally, there appears to be a role for neuroinflammation in aggravating tau pathology and neurodegeneration in tauopathies featuring tau deposits as the predominant pathological signature. In this review, we survey the literature regarding inflammatory mechanisms that may impact neurodegeneration in AD and related tauopathies. We consider a physical role for microglia in the spread of tau pathology as well as the non-cell autonomous effects of secreted proinflammatory cytokines, specifically interleukin 1 beta, interleukin 6, tumor necrosis factor alpha and complement proteins. These molecules appear to have direct effects on tau pathophysiology and overall neuronal health. They also indirectly impact neuronal homeostasis by altering glial function. We conclude by proposing a complex role for gliosis and neuroinflammation in accelerating the progression of AD and other tauopathies.
- An analogous pattern has been recapitulated in two independent mouse models, rTgECtau mice, where mutant tau was exclusively expressed in the entorhinal cortex and neurons containing aggregates but lacking tau mRNA were found downstream in the dentate gyrus and hippocampus[43,44]. Similar temporal progression of tau pathology is observed in AGD, though the brain regions involved differ. Likewise, the spatial distribution of tangles is distinct in other tauopathies[1,2]indicating additional mechanisms involving the vulnerability of certain neuronal populations contribute to disease.
[Show abstract] [Hide abstract] ABSTRACT: To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients. These findings are critically important for the rational development of stem-cell-based dopamine neuronal replacement therapies for PD.
- It has been suggested that such Lewybody-like pathology is a product of protein transfer from the parkinsonian host brain to the transplanted fetal cells (Kurowska et al., 2011). However, a-synuclein pathology is not definitive for PD, and incidental a-synuclein pathology has also been reported in the normal aging brain, with frequencies of 8%–22.5% in normal aging and up to 34.8% in centenarians (Ding et al., 2006; Klos et al., 2006; Mikolaenko et al., 2005; Saito et al., 2004; Wakisaka et al., 2003). Experimental paradigms of oxidative stress (e.g., rotenone exposure) or neuroinflammation can also induce a-synuclein accumulation in dopamine neurons (Gao et al., 2008; Sherer et al., 2003).