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Papers by Kazunari Sekiyama

Journal of Neurology, Aug 1, 2009

Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for... more Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as alpha-syn deposits, compromised function of dopaminergic neurons, fibrillization of alpha-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of alpha-syn tg mice may be required. We predict that beta-synuclein (beta-syn), the homologue of alpha-syn, might be a key molecule for this purpose. Although beta-syn is a neuroprotective molecule counteracting the alpha-syn pathology in tg mice, it was previously shown that both beta-syn and gamma-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson's disease and DLB. Furthermore, two missense mutations (P123H and V70M) of beta-syn were recently identified in DLB. These mutants of beta-syn were prone to aggregate in vitro and overexpression of these mutant beta-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of beta-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant beta-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional alpha-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant beta-syn/alpha-syn might be characterized by a more accelerated phenotype of synucleinopathies.

Parkinson's Disease, 2012

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with altera... more Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation in α-synuclein (αS) transgenic and related model mice. In the majority of αS transgenic mice, astrogliosis was observed concomitantly with accumulation of αS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results in αS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression.

Biochemical and Biophysical Research Communications, Mar 1, 2006

Activins, TGF-b superfamily members, have multiple functions in a variety of cells and tissues. R... more Activins, TGF-b superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin b subunit genes, bC and bE, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin bE subunit. There were pronounced differences in the pancreata of the transgenic animals as compared with their wild-type counterparts. Pancreatic weight, expressed relative to total body weight, was significantly reduced. Histologically, adipose replacement of acini in the exocrine pancreas was observed. There was a significant decrease in the number of PCNA-positive cells in the acinar cells, indicating reduced proliferation in the exocrine pancreas of the transgenic mice. However, quantitative pancreatic morphometry showed that the total number and mass of the islets of the transgenic mice were comparable with those of the nontransgenic control mice. Our findings suggest a role for activin E in regulating the proliferation of pancreatic exocrine cells.

The Royal Society of Chemistry eBooks, Jul 29, 2013

Neurodegenerative diseases such as Parkinson’s disease (PD) and prion disease are characterized b... more Neurodegenerative diseases such as Parkinson’s disease (PD) and prion disease are characterized by protein aggregation and gliosis, including astrocytes and microglia. Currently, there is no treatment for prevention of disease progression. It has been well characterized that neuroinflammation caused by aberrant activation of glial cells may play a critical role in the pathogenesis of neurodegenerative diseases, and thus modulation of neuroinflammatory reactions may be a possible therapeutic strategy. In this context, we focus here on the P2X7 receptor (P2X7R), a cation‐selective ion channel gated by extracellular adenosine triphosphate, as a drug target for the modulation of neuroinflammation in PD. P2X7R is highly expressed in microglia in the central nervous system and has a pivotal role in the maturation and release of the powerful pro‐inflammatory cytokine interleukin‐1β (IL‐1β). Importantly, increased expression of IL‐1β correlates with the progression of PD, and up‐regulation of P2X7R expression is also observed in animal models of PD. Furthermore, evidence is accumulating to indicate that P2X7R may be involved in a variety of cellular events that lead to both neurodegeneration and neuroprotection. Thus, drugs that modulate P2X7R activity may provide a new strategy for treatment of Parkinson’s and other neurodegenerative diseases.

Oxidative Medicine and Cellular Longevity, 2013

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of-synucle... more There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD,-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained in Drosophila and cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressing-synuclein or DLB-linked P123H-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated in-synuclein/LRRK2-immunopositive axonal swellings in mice expressing-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123H-synuclein, suggesting thatand-synuclein might play differential roles in the mitochondrial pathology of-synucleinopathies.

Journal of Veterinary Medical Science, 2019

Activin E, a secreted peptide encoded by the inhibin/activin βE subunit gene, is a member of the ... more Activin E, a secreted peptide encoded by the inhibin/activin βE subunit gene, is a member of the transforming growth factor-β superfamily, which is predominantly expressed in the liver. Recent reports have suggested that activin E plays a role in energy homeostasis as a hepatokine. Here, using transgenic mice overexpressing activin E under the control of the β-actin promoter, we demonstrate that activin E controls energy metabolism through brown/beige adipocytes. The glucose tolerance test and insulin tolerance test showed that the insulin sensitivity was improved in the transgenic mice. Furthermore, the mice had a high body temperature compared with wild-type mice. The transgenic brown adipose tissue and mesenteric white adipose tissue showed upregulation of uncoupling protein 1, which enables energy dissipation as heat by uncoupling oxidative phosphorylation from ATP production. Present results indicate that activin E activates energy expenditure through brown/beige adipocyte activation, suggesting that activin E has high potential for obesity therapy.

Expert Opinion on Medical Diagnostics, Nov 4, 2012

Parkinson&amp... more Parkinson's disease (PD) is the most common neurodegenerative disease leading to movement disorders, and is characterized neuropathologically by the progressive loss of dopaminergic neurons, intracellular α-synuclein deposition and the formation of Lewy bodies. The difficulty of making a definitive diagnosis of PD itself, as opposed to other neurodegenerative diseases associated with parkinsonism, is a central issue in clinical PD research. However, recent advances in diagnostic methods, encompassing imaging techniques, genetic testing and measurement of biological markers may permit earlier diagnosis, and thus potentially improved management of PD. In addition to clinical symptoms and imaging techniques, a number of genetic and biological markers obtained from body fluids such as cerebrospinal fluids may hold promise for the early detection of PD. It is often difficult to make an accurate diagnosis and to distinguish PD from other diseases with features of parkinsonism, particularly during the early stages of the disease. In this regard, biomarkers which are specific for PD, in combination with observation of clinical symptoms, may facilitate the early diagnosis and improved management of PD. Good biomarkers for PD could be helpful for early diagnosis, management and tracking of disease progression. Furthermore, combined analysis using several kinds of biomarkers may allow the detection of preclinical PD, which in turn may facilitate a prevention of disease onset with the use of disease-modifying drugs.

Biochemical and Biophysical Research Communications, Sep 1, 2014

Research on Parkinson&amp... more Research on Parkinson's disease (PD) has made remarkable progress in recent decades, due largely to new genomic technologies, such as high throughput sequencing and microarray analyses. Since the discovery of a linkage of a missense mutation of the α-synuclein (αS) gene to a rare familial dominant form of PD in 1996, positional cloning and characterization of a number of familial PD risk factors have established a hypothesis that aggregation of αS may play a major role in the pathogenesis of PD. Furthermore, dozens of sensitizing alleles related to the disease have been identified by genome wide association studies (GWAS) and meta-GWAS, contributing to a better understanding of the pathological mechanisms of sporadic PD. Thus, the knowledge obtained from the association studies will be valuable for "the personal genome" of PD. Besides summarizing such progress, this paper focuses on the role of microRNAs in the field of PD research, since microRNAs might be promising as a biomarker and as a therapeutic reagent for PD. We further refer to a recent view that neurodegenerative diseases, including PD, coexist with metabolic disorders and are stimulated by type II diabetes, the most common disease among elderly populations. The development of genomic approaches may potentially contribute to therapeutic intervention for PD.

International Journal of Molecular Sciences, Sep 14, 2012

α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline... more α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. α-Synuclein (αS) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. β-Synuclein (βS), the non-amyloidogenic homologue of αS, ameliorates the neurodegeneration phenotype of αS in transgenic (tg) mouse models, as well as in cell free and cell culture systems, which suggests that βS might be a negative regulator of neurodegeneration caused by αS, and that "loss of function" of βS might be involved in progression of α-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS develop progressive neurodegeneration phenotypes, such as axonal pathology and dementia. In this short review, we emphasize the aspects of "toxic gain of function" of wild type βS during the pathogenesis of sporadic α-synucleinopathies.

Neuroscience Letters, Apr 1, 2012

Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduce... more Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduces the risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this context, it has been shown that chronic treatment with ibuprofen improves cognitive dysfunction and histopathologic outcome in mouse models of AD. However, the therapeutic effects of ibuprofen in animal models of PD and related synucleinopathies such as dementia with Lewy bodies (DLB) have not been investigated. Therefore, the main objective of this study was to determine if ibuprofen ameliorates neuropathology and cognitive dysfunction in a transgenic (tg) mouse expressing DLB-linked P123H ␤synuclein. P123H ␤-synuclein tg mice and their non-tg littermates aged 3 months were given ibuprofen in their diet (n = 13). Controls did not receive ibuprofen (n = 11). After 3 months, the mice were evaluated using a Morris water maze test, followed by neuropathological analyses. Compared to control P123H ␤synuclein tg mice, P123H ␤-synuclein tg mice that received ibuprofen had significantly reduced protein aggregation and astrogliosis. However, ibuprofen treatment produced little improvement of the learning disability of P123H ␤-synuclein tg mice in the Morris water maze test. These results suggest that amelioration of neuropathologies by ibuprofen does not necessarily lead to improved cognitive function in synucleinopathies such as DLB.

Neuroscience Research, Sep 1, 2011

As typified by Parkinson's disease, Lewy body dementia (DLB) and Alzheimer's disease, neurodegene... more As typified by Parkinson's disease, Lewy body dementia (DLB) and Alzheimer's disease, neurodegenerative diseases bring on cell death and synapse loss. Hence, dementia and motor dysfunction are caused. However, the processes of synapse loss and axonal degeneration in neurodegenerative disease have been still incompletely understood. Previous studies showed that administration of ganglioside GM1 does not protect against cell death but exert a protective effect dopamine level and optical density values of tyrosine hydroxylase-immunoreactive fibers in MPTP-treated monkeys. This phenomenon indicates that cell death do not equal axonal degeneration. So, how do the axons in neurodegenerative disease lose synapses and retract? The aim of this study was to understand the early process of synaptic loss and axon degeneration in ␣-synucleinopathy. We used aged transgenic mice overexpressing human ␣-synuclein (␣S) and analyzed axon terminals morphologically. In this mouse, GABAergic cells in striatum, thalamus and olfactory tubercle made axonal swellings. The long axes of these structures were less than 10 m. We called it "globule". In the globules, mitochondria accumulated and were deformed to abnormal shape, e.g. chondriospheres and myelin figure, like in tumor. Additionally, immunoreactivities of lysosome marker, ganglioside GM3 and GD3, intermediary metabolite of ganglioside GD1a and GT1b, appeared in globules. Interestingly, microstructures of globules showed not only ␣S-immunopositive multivesicular body, but also curvilinear body and fingerprint profiles. On the other hand, in ␣S-overexpressed somata, there was not deformed mitochondria and amorphous bilayer membranes. The observations in ␣S transgenic mouse axon were similar to the pathology of neuronal ceroid lipofuscinosis. This study showed that ␣S overexpression and terminal accumulation was inducible breakdown of local lysosome-dependent lipid degradative pathway.

Biochemical and Biophysical Research Communications, Jul 1, 2009

To study the function of activin E, a TGF-beta superfamily member, in the regulation of affective... more To study the function of activin E, a TGF-beta superfamily member, in the regulation of affective behavior, we investigated the behavior of transgenic mice overexpressing activin E (TgActbetaE mice). Male TgActbetaE mice showed aggressive behavior in resident-intruder tests. In elevated plus-maze tests, the percentage of open arm entries was significantly increased in female TgActbetaE mice compared with that in wild-type mice. Furthermore, female TgActbetaE mice stayed in the central area for a significantly longer time than wild-type mice in open field tests. These results indicated that TgActbetaE mice had less anxiety-like behavior. The number of restraint-stress-evoked c-Fos-positive cells in the hypothalamic paraventricular nucleus in TgActbetaE mice was significantly decreased compared with that in wild-type mice. This suggests that synthesis of corticotrophin-releasing hormone induced by stress was decreased in TgActbetaE mice. Taking these results together, activin E may act as a regulator of the hypothalamic-pituitary-adrenal axis.

Neuroscience Research, 2009

s S245 affected by this molecule. Resveratrol reduced lipid peroxide in serum, lipid droplets in ... more s S245 affected by this molecule. Resveratrol reduced lipid peroxide in serum, lipid droplets in hepatocytes, and activated phagocytosis of Kupffer cells. In the CNS, resveratrol reduced the appearance of lipofuscin granules, a marker for the aging, enhanced expressions of synaptophysin, superoxide dismutase, Bcl-2 and Bcl-xL connected with activation of neuronal function, and decreased neurofilament proteins, GFAP and Bax involved in aging/neurodegeneration. Together, resveratrol may function as beneficial to the CNS and protecting neurons from aging or degeneration. doi:10.1016/j.neures.2009.09.1385 P3-l10 Rhizoma (Senkyu), one of various components of Yokukansan reduced the ER stress induced cell toxicity resulting in the good effect on the Alzheimer disease associated cell death Toru Hiratsuka1, Shinsuke Matsuzaki2, Shingo Miyata1, Taiichi Katayama2, Masaya Tohyama1,2 1 Dept. Anat&Neurosci, University of Osaka, Osaka, Japan; 2 United Grad. Sch. of Child Develop, Osaka Univ., Kanazawa University, Hamamatsu Univ. Sch. of Med., Osaka, Japan Yokukansan has been administrated to the persons who show such symptoms as nervousness etc. Yokukansan is focused as the one of the possible therapies for Alzheimer’s disease (AD). ER stress plays an important role in the pathogenesis of AD. Thus, we examined the effect of yokukansan on the ER stress induced neurotoxicity and the familial AD-linked PS1 mutation ( E9) associated cell death to investigate the effects of yokukansan on the AD linked cell death. As results, we elucidated that yokukansan should upregulate the expression of GRP78 and reduce the expression of CHOP resulting in the reduction of ER stress induced cell death and the AD-linked associated cell death. These results suggest that yokukansan and Rhizoma should be potential medicine to the AD and our findings cast new light on the development of therapy for the AD. doi:10.1016/j.neures.2009.09.1386 P3-l11 Aged Alzheimer mice bear the increased expression of diazepam binding inhibitor in activated glial cells Kota Kimura, Mayu Shimatani, Jun Kaneko, Kaori Taniguchi, Ken Aizawa, Tatsuhiro Hisatsune Dept. Integrated., The University of Tokyo, Tokyo, Japan In Alzheimer disease, the change in glial functions has become a current attention in terms of both pathogenesis and therapeutic applications. In a related study, we also report the increased proliferation of astroglial cells at the dentate gyrus of hippocampal formation in the transgenic mice B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J as a model for Alzheimer disease. In this study, we evaluated the expression of diazepam biding inhibitor (DBI) in the activated astroglial cells. A recent report showed that the over-expression of DBI caused the cognitive decline as assessed by hippocampal dependent behavior task and the deficit in LTP function of hippocampal circuit (Siiskonen et al., 2007). Very interestingly, we observed the increased expression of DBI in astroglial cells at the hilar region of Alzheimer transgenic mice, but not in those of control wild-type littermate, after 12 months of ages. Our results may suggest that the functional changes in hippocampal glial cells would be involved in the cognitive deficit in Alzheimer disease. doi:10.1016/j.neures.2009.09.1387 P3-l12 Identification of protein targets for 15-deoxy12,14prostaglandin J2 in neuronal plasma membranes Tatsurou Yagami, Kenkichi Takase, Yasuhiro Yamamoto Dept. Physiol., Facult. Pharmath. Sci., Himeji Dokkyo Univ., Himeji, Japan Deposits of amyloid protein (A ) are generally assumed to contribute to progressive neurodegeneration in the Alzheimer’s disease (AD). In primary cultures of cortical neurons, A significantly generated prostaglandin D2 (PGD2) before cell death. Although PGD2 induced neuronal cell death, specific binding sites of [H]PGD2 were not detected in plasma membranes. Without enzymes, PGD2 was metabolized to 15-deoxy12,14-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 was more neurotoxic than PGD2. The specific binding sites of [3H]15d-PGJ2 were abundant in plasma membranes. A proteomic approach was used to identify protein targets for 15d-PGJ2 in neuronal plasma membranes. By using biotinylated 15d-PGJ2, 21 proteins were identified as biotin-positive targets. They were classified into cytoskeltal proteins, glycolytic enzymes and molecular chaperones. Some of these targets have been reported to interact with A and associate with AD. doi:10.1016/j.neures.2009.09.1388 P3-l13 Molecular mechanisms to form insoluble complex in a mouse model of multiple system atrophy (MSA) Kimiko Nakayama, Yasuyo Suzuki, Ikuru Yazawa Laboratory of Research Resources, National Center for Geriatrics and Geron-

Annals of Neurology, Jul 1, 2013

Molecular Brain, Sep 26, 2012

Background: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, inclu... more Background: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice. Results: In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules. Conclusions: Lysosomal pathology was similarly observed for both αSand P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αSand P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

Journal of Alzheimer's Disease, Jun 7, 2016

Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of A... more Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

npj Parkinson's disease, Jan 23, 2017

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicit... more Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid β monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "antiinsulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy.

Alzheimers & Dementia, Jul 1, 2015

Journal of Neurology, Aug 1, 2009

Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for... more Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as alpha-syn deposits, compromised function of dopaminergic neurons, fibrillization of alpha-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of alpha-syn tg mice may be required. We predict that beta-synuclein (beta-syn), the homologue of alpha-syn, might be a key molecule for this purpose. Although beta-syn is a neuroprotective molecule counteracting the alpha-syn pathology in tg mice, it was previously shown that both beta-syn and gamma-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson's disease and DLB. Furthermore, two missense mutations (P123H and V70M) of beta-syn were recently identified in DLB. These mutants of beta-syn were prone to aggregate in vitro and overexpression of these mutant beta-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of beta-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant beta-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional alpha-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant beta-syn/alpha-syn might be characterized by a more accelerated phenotype of synucleinopathies.

Parkinson's Disease, 2012

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with altera... more Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation in α-synuclein (αS) transgenic and related model mice. In the majority of αS transgenic mice, astrogliosis was observed concomitantly with accumulation of αS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results in αS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression.

Biochemical and Biophysical Research Communications, Mar 1, 2006

Activins, TGF-b superfamily members, have multiple functions in a variety of cells and tissues. R... more Activins, TGF-b superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin b subunit genes, bC and bE, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin bE subunit. There were pronounced differences in the pancreata of the transgenic animals as compared with their wild-type counterparts. Pancreatic weight, expressed relative to total body weight, was significantly reduced. Histologically, adipose replacement of acini in the exocrine pancreas was observed. There was a significant decrease in the number of PCNA-positive cells in the acinar cells, indicating reduced proliferation in the exocrine pancreas of the transgenic mice. However, quantitative pancreatic morphometry showed that the total number and mass of the islets of the transgenic mice were comparable with those of the nontransgenic control mice. Our findings suggest a role for activin E in regulating the proliferation of pancreatic exocrine cells.

The Royal Society of Chemistry eBooks, Jul 29, 2013

Neurodegenerative diseases such as Parkinson’s disease (PD) and prion disease are characterized b... more Neurodegenerative diseases such as Parkinson’s disease (PD) and prion disease are characterized by protein aggregation and gliosis, including astrocytes and microglia. Currently, there is no treatment for prevention of disease progression. It has been well characterized that neuroinflammation caused by aberrant activation of glial cells may play a critical role in the pathogenesis of neurodegenerative diseases, and thus modulation of neuroinflammatory reactions may be a possible therapeutic strategy. In this context, we focus here on the P2X7 receptor (P2X7R), a cation‐selective ion channel gated by extracellular adenosine triphosphate, as a drug target for the modulation of neuroinflammation in PD. P2X7R is highly expressed in microglia in the central nervous system and has a pivotal role in the maturation and release of the powerful pro‐inflammatory cytokine interleukin‐1β (IL‐1β). Importantly, increased expression of IL‐1β correlates with the progression of PD, and up‐regulation of P2X7R expression is also observed in animal models of PD. Furthermore, evidence is accumulating to indicate that P2X7R may be involved in a variety of cellular events that lead to both neurodegeneration and neuroprotection. Thus, drugs that modulate P2X7R activity may provide a new strategy for treatment of Parkinson’s and other neurodegenerative diseases.

Oxidative Medicine and Cellular Longevity, 2013

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of-synucle... more There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD,-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained in Drosophila and cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressing-synuclein or DLB-linked P123H-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated in-synuclein/LRRK2-immunopositive axonal swellings in mice expressing-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123H-synuclein, suggesting thatand-synuclein might play differential roles in the mitochondrial pathology of-synucleinopathies.

Journal of Veterinary Medical Science, 2019

Activin E, a secreted peptide encoded by the inhibin/activin βE subunit gene, is a member of the ... more Activin E, a secreted peptide encoded by the inhibin/activin βE subunit gene, is a member of the transforming growth factor-β superfamily, which is predominantly expressed in the liver. Recent reports have suggested that activin E plays a role in energy homeostasis as a hepatokine. Here, using transgenic mice overexpressing activin E under the control of the β-actin promoter, we demonstrate that activin E controls energy metabolism through brown/beige adipocytes. The glucose tolerance test and insulin tolerance test showed that the insulin sensitivity was improved in the transgenic mice. Furthermore, the mice had a high body temperature compared with wild-type mice. The transgenic brown adipose tissue and mesenteric white adipose tissue showed upregulation of uncoupling protein 1, which enables energy dissipation as heat by uncoupling oxidative phosphorylation from ATP production. Present results indicate that activin E activates energy expenditure through brown/beige adipocyte activation, suggesting that activin E has high potential for obesity therapy.

Expert Opinion on Medical Diagnostics, Nov 4, 2012

Parkinson&amp... more Parkinson's disease (PD) is the most common neurodegenerative disease leading to movement disorders, and is characterized neuropathologically by the progressive loss of dopaminergic neurons, intracellular α-synuclein deposition and the formation of Lewy bodies. The difficulty of making a definitive diagnosis of PD itself, as opposed to other neurodegenerative diseases associated with parkinsonism, is a central issue in clinical PD research. However, recent advances in diagnostic methods, encompassing imaging techniques, genetic testing and measurement of biological markers may permit earlier diagnosis, and thus potentially improved management of PD. In addition to clinical symptoms and imaging techniques, a number of genetic and biological markers obtained from body fluids such as cerebrospinal fluids may hold promise for the early detection of PD. It is often difficult to make an accurate diagnosis and to distinguish PD from other diseases with features of parkinsonism, particularly during the early stages of the disease. In this regard, biomarkers which are specific for PD, in combination with observation of clinical symptoms, may facilitate the early diagnosis and improved management of PD. Good biomarkers for PD could be helpful for early diagnosis, management and tracking of disease progression. Furthermore, combined analysis using several kinds of biomarkers may allow the detection of preclinical PD, which in turn may facilitate a prevention of disease onset with the use of disease-modifying drugs.

Biochemical and Biophysical Research Communications, Sep 1, 2014

Research on Parkinson&amp... more Research on Parkinson's disease (PD) has made remarkable progress in recent decades, due largely to new genomic technologies, such as high throughput sequencing and microarray analyses. Since the discovery of a linkage of a missense mutation of the α-synuclein (αS) gene to a rare familial dominant form of PD in 1996, positional cloning and characterization of a number of familial PD risk factors have established a hypothesis that aggregation of αS may play a major role in the pathogenesis of PD. Furthermore, dozens of sensitizing alleles related to the disease have been identified by genome wide association studies (GWAS) and meta-GWAS, contributing to a better understanding of the pathological mechanisms of sporadic PD. Thus, the knowledge obtained from the association studies will be valuable for "the personal genome" of PD. Besides summarizing such progress, this paper focuses on the role of microRNAs in the field of PD research, since microRNAs might be promising as a biomarker and as a therapeutic reagent for PD. We further refer to a recent view that neurodegenerative diseases, including PD, coexist with metabolic disorders and are stimulated by type II diabetes, the most common disease among elderly populations. The development of genomic approaches may potentially contribute to therapeutic intervention for PD.

International Journal of Molecular Sciences, Sep 14, 2012

α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline... more α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. α-Synuclein (αS) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. β-Synuclein (βS), the non-amyloidogenic homologue of αS, ameliorates the neurodegeneration phenotype of αS in transgenic (tg) mouse models, as well as in cell free and cell culture systems, which suggests that βS might be a negative regulator of neurodegeneration caused by αS, and that "loss of function" of βS might be involved in progression of α-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS develop progressive neurodegeneration phenotypes, such as axonal pathology and dementia. In this short review, we emphasize the aspects of "toxic gain of function" of wild type βS during the pathogenesis of sporadic α-synucleinopathies.

Neuroscience Letters, Apr 1, 2012

Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduce... more Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduces the risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this context, it has been shown that chronic treatment with ibuprofen improves cognitive dysfunction and histopathologic outcome in mouse models of AD. However, the therapeutic effects of ibuprofen in animal models of PD and related synucleinopathies such as dementia with Lewy bodies (DLB) have not been investigated. Therefore, the main objective of this study was to determine if ibuprofen ameliorates neuropathology and cognitive dysfunction in a transgenic (tg) mouse expressing DLB-linked P123H ␤synuclein. P123H ␤-synuclein tg mice and their non-tg littermates aged 3 months were given ibuprofen in their diet (n = 13). Controls did not receive ibuprofen (n = 11). After 3 months, the mice were evaluated using a Morris water maze test, followed by neuropathological analyses. Compared to control P123H ␤synuclein tg mice, P123H ␤-synuclein tg mice that received ibuprofen had significantly reduced protein aggregation and astrogliosis. However, ibuprofen treatment produced little improvement of the learning disability of P123H ␤-synuclein tg mice in the Morris water maze test. These results suggest that amelioration of neuropathologies by ibuprofen does not necessarily lead to improved cognitive function in synucleinopathies such as DLB.

Neuroscience Research, Sep 1, 2011

As typified by Parkinson's disease, Lewy body dementia (DLB) and Alzheimer's disease, neurodegene... more As typified by Parkinson's disease, Lewy body dementia (DLB) and Alzheimer's disease, neurodegenerative diseases bring on cell death and synapse loss. Hence, dementia and motor dysfunction are caused. However, the processes of synapse loss and axonal degeneration in neurodegenerative disease have been still incompletely understood. Previous studies showed that administration of ganglioside GM1 does not protect against cell death but exert a protective effect dopamine level and optical density values of tyrosine hydroxylase-immunoreactive fibers in MPTP-treated monkeys. This phenomenon indicates that cell death do not equal axonal degeneration. So, how do the axons in neurodegenerative disease lose synapses and retract? The aim of this study was to understand the early process of synaptic loss and axon degeneration in ␣-synucleinopathy. We used aged transgenic mice overexpressing human ␣-synuclein (␣S) and analyzed axon terminals morphologically. In this mouse, GABAergic cells in striatum, thalamus and olfactory tubercle made axonal swellings. The long axes of these structures were less than 10 m. We called it "globule". In the globules, mitochondria accumulated and were deformed to abnormal shape, e.g. chondriospheres and myelin figure, like in tumor. Additionally, immunoreactivities of lysosome marker, ganglioside GM3 and GD3, intermediary metabolite of ganglioside GD1a and GT1b, appeared in globules. Interestingly, microstructures of globules showed not only ␣S-immunopositive multivesicular body, but also curvilinear body and fingerprint profiles. On the other hand, in ␣S-overexpressed somata, there was not deformed mitochondria and amorphous bilayer membranes. The observations in ␣S transgenic mouse axon were similar to the pathology of neuronal ceroid lipofuscinosis. This study showed that ␣S overexpression and terminal accumulation was inducible breakdown of local lysosome-dependent lipid degradative pathway.

Biochemical and Biophysical Research Communications, Jul 1, 2009

To study the function of activin E, a TGF-beta superfamily member, in the regulation of affective... more To study the function of activin E, a TGF-beta superfamily member, in the regulation of affective behavior, we investigated the behavior of transgenic mice overexpressing activin E (TgActbetaE mice). Male TgActbetaE mice showed aggressive behavior in resident-intruder tests. In elevated plus-maze tests, the percentage of open arm entries was significantly increased in female TgActbetaE mice compared with that in wild-type mice. Furthermore, female TgActbetaE mice stayed in the central area for a significantly longer time than wild-type mice in open field tests. These results indicated that TgActbetaE mice had less anxiety-like behavior. The number of restraint-stress-evoked c-Fos-positive cells in the hypothalamic paraventricular nucleus in TgActbetaE mice was significantly decreased compared with that in wild-type mice. This suggests that synthesis of corticotrophin-releasing hormone induced by stress was decreased in TgActbetaE mice. Taking these results together, activin E may act as a regulator of the hypothalamic-pituitary-adrenal axis.

Neuroscience Research, 2009

s S245 affected by this molecule. Resveratrol reduced lipid peroxide in serum, lipid droplets in ... more s S245 affected by this molecule. Resveratrol reduced lipid peroxide in serum, lipid droplets in hepatocytes, and activated phagocytosis of Kupffer cells. In the CNS, resveratrol reduced the appearance of lipofuscin granules, a marker for the aging, enhanced expressions of synaptophysin, superoxide dismutase, Bcl-2 and Bcl-xL connected with activation of neuronal function, and decreased neurofilament proteins, GFAP and Bax involved in aging/neurodegeneration. Together, resveratrol may function as beneficial to the CNS and protecting neurons from aging or degeneration. doi:10.1016/j.neures.2009.09.1385 P3-l10 Rhizoma (Senkyu), one of various components of Yokukansan reduced the ER stress induced cell toxicity resulting in the good effect on the Alzheimer disease associated cell death Toru Hiratsuka1, Shinsuke Matsuzaki2, Shingo Miyata1, Taiichi Katayama2, Masaya Tohyama1,2 1 Dept. Anat&Neurosci, University of Osaka, Osaka, Japan; 2 United Grad. Sch. of Child Develop, Osaka Univ., Kanazawa University, Hamamatsu Univ. Sch. of Med., Osaka, Japan Yokukansan has been administrated to the persons who show such symptoms as nervousness etc. Yokukansan is focused as the one of the possible therapies for Alzheimer’s disease (AD). ER stress plays an important role in the pathogenesis of AD. Thus, we examined the effect of yokukansan on the ER stress induced neurotoxicity and the familial AD-linked PS1 mutation ( E9) associated cell death to investigate the effects of yokukansan on the AD linked cell death. As results, we elucidated that yokukansan should upregulate the expression of GRP78 and reduce the expression of CHOP resulting in the reduction of ER stress induced cell death and the AD-linked associated cell death. These results suggest that yokukansan and Rhizoma should be potential medicine to the AD and our findings cast new light on the development of therapy for the AD. doi:10.1016/j.neures.2009.09.1386 P3-l11 Aged Alzheimer mice bear the increased expression of diazepam binding inhibitor in activated glial cells Kota Kimura, Mayu Shimatani, Jun Kaneko, Kaori Taniguchi, Ken Aizawa, Tatsuhiro Hisatsune Dept. Integrated., The University of Tokyo, Tokyo, Japan In Alzheimer disease, the change in glial functions has become a current attention in terms of both pathogenesis and therapeutic applications. In a related study, we also report the increased proliferation of astroglial cells at the dentate gyrus of hippocampal formation in the transgenic mice B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J as a model for Alzheimer disease. In this study, we evaluated the expression of diazepam biding inhibitor (DBI) in the activated astroglial cells. A recent report showed that the over-expression of DBI caused the cognitive decline as assessed by hippocampal dependent behavior task and the deficit in LTP function of hippocampal circuit (Siiskonen et al., 2007). Very interestingly, we observed the increased expression of DBI in astroglial cells at the hilar region of Alzheimer transgenic mice, but not in those of control wild-type littermate, after 12 months of ages. Our results may suggest that the functional changes in hippocampal glial cells would be involved in the cognitive deficit in Alzheimer disease. doi:10.1016/j.neures.2009.09.1387 P3-l12 Identification of protein targets for 15-deoxy12,14prostaglandin J2 in neuronal plasma membranes Tatsurou Yagami, Kenkichi Takase, Yasuhiro Yamamoto Dept. Physiol., Facult. Pharmath. Sci., Himeji Dokkyo Univ., Himeji, Japan Deposits of amyloid protein (A ) are generally assumed to contribute to progressive neurodegeneration in the Alzheimer’s disease (AD). In primary cultures of cortical neurons, A significantly generated prostaglandin D2 (PGD2) before cell death. Although PGD2 induced neuronal cell death, specific binding sites of [H]PGD2 were not detected in plasma membranes. Without enzymes, PGD2 was metabolized to 15-deoxy12,14-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 was more neurotoxic than PGD2. The specific binding sites of [3H]15d-PGJ2 were abundant in plasma membranes. A proteomic approach was used to identify protein targets for 15d-PGJ2 in neuronal plasma membranes. By using biotinylated 15d-PGJ2, 21 proteins were identified as biotin-positive targets. They were classified into cytoskeltal proteins, glycolytic enzymes and molecular chaperones. Some of these targets have been reported to interact with A and associate with AD. doi:10.1016/j.neures.2009.09.1388 P3-l13 Molecular mechanisms to form insoluble complex in a mouse model of multiple system atrophy (MSA) Kimiko Nakayama, Yasuyo Suzuki, Ikuru Yazawa Laboratory of Research Resources, National Center for Geriatrics and Geron-

Annals of Neurology, Jul 1, 2013

Molecular Brain, Sep 26, 2012

Background: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, inclu... more Background: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice. Results: In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules. Conclusions: Lysosomal pathology was similarly observed for both αSand P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αSand P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

Journal of Alzheimer's Disease, Jun 7, 2016

Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of A... more Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

npj Parkinson's disease, Jan 23, 2017

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicit... more Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid β monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "antiinsulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy.

Alzheimers & Dementia, Jul 1, 2015