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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.

Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin βE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, in vitro experiments suggested that activin E directly stimulated expression of Ucp1 and Fgf21, which was mediated by transforming growth factor-β or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity., アクチビンEが脂肪燃焼細胞の増加を促進することを解明 --肥満解消の新たなプレイヤーを発見--. 京都大学プレスリリース. 2018-11-02.

A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both ‘gain of function’ and ‘loss of function’ of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

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.

Recent clinical trials using immunization approaches against Alzheimer's disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior that is resilient and resistant to therapeutic stimuli. Notably, such a 'discrepancy between histology and behavior' is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that 'the discrepancy between histology and behavior' may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand 'the discrepancy between histology and behavior' in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8 h/day, 5 days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2 weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16 weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD.

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.

Objective Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the antidiabetes protein, in the pathogenesis of α-synucleinopathies. Methods Using biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies. Results We observed that APN is localized in Lewy bodies derived from α-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine and inosine monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN. Interpretation Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis ofα-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,α-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 inDrosophilaand cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressingα-synuclein or DLB-linked P123Hβ-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated inα-synuclein/LRRK2-immunopositive axonal swellings in mice expressingα-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123Hβ-synuclein, suggesting thatα- andβ-synuclein might play differential roles in the mitochondrial pathology ofα-synucleinopathies.

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.

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.

Parkinson’s disease (PD) is the most common form of movement disorder and affects approximately 4% of the population aged over 80 years old. Currently, PD cannot be prevented or cured, and no single diagnostic biomarkers are available. Notably, recent studies suggest that two familial PD-linked molecules, α-synuclein and DJ-1, are present in cerebrospinal fluid (CSF) and that their levels may be altered during the progression of PD. In this regard, sensitive and accurate methods for evaluation of α-synuclein and DJ-1 levels in the CSF and blood have been developed, and the results suggest that the levels of both molecules are significantly decreased in the CSF in patients with PD compared with age-matched controls. Furthermore, specific detection and quantification of neurotoxic oligometric forms of α-synuclein in the blood using enzyme-linked immunosorbent assays might be expected as potential peripheral biomarkers for PD, although further validation is required. Currently, neither α-synuclein nor DJ-1 is satisfactory as a single biomarker for PD, but combinatory evaluation of these biological fluid molecules with other biomarkers and imaging techniques may provide reliable information for diagnosis of PD.

Aims Activin E is a newly identified member of the transforming growth factor-β superfamily. To assess the role of activin E in glucose/energy metabolism, we investigated the transcriptional regulation of activin E in the liver. Main methods Northern blotting, Western blotting, quantitative real-time polymerase chain reaction (PCR), reporter assays and chromatin immunoprecipitation assays were used in this study. Key findings Insulin up-regulated activin E expression at the mRNA and protein level in HepG2 cells. Reporter assays revealed that the putative, functional, promoter sequence of human activin E gene was responsible for the effect of insulin. Mutational analysis of the promoter revealed that CCAAT/enhancer-binding proteins (C/EBPs) play a key role in regulating activin E expression and in the stimulatory effect of insulin on activin E transcription. Chromatin immunoprecipitation assays revealed that the C/EBPs can bind to the activin E promoter in HepG2 cells. The expression of activin E mRNA was up-regulated in the liver of diet-induced obese mice. Significance These observations suggest that activin E plays a pathophysiological role in glucose metabolism.

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.

All living organisms have evolutionarily adapted themselves to the Earth's gravity, and failure to adapt to gravity changes may lead to pathological conditions. This perspective may also apply to abnormal aging observed in bedridden elderly patients with aging-associated diseases such as osteoporosis and sarcopenia. Given that bedridden elderly patients are partially analogous to astronauts in that both cannot experience the beneficial effects of gravity on the skeletal system and may suffer from bone loss and muscle weakness, one may wonder whether there are gravity-related mechanisms underlying diseases among the elderly. In contrast to numerous studies of the relevance of microgravity in skeletal disorders, little attention has been paid to neurodegenerative diseases. Therefore, the objective of this paper is to discuss the possible relevance of microgravity in these diseases. We particularly noted a proteomics paper showing that levels of hippocampal proteins, including β-synuclein and carboxyl-terminal ubiquitin hydrolase L1, which have been linked to familial neurodegenerative diseases, were significantly decreased in the hippocampus of mice subjected to hindlimb suspension, a model of microgravity. We suggest that microgravity-induced neurodegeneration may be further exacerbated by diabetes and other factors. On the basis of this view, prevention of neurodegenerative diseases through 'anti-diabetes' and 'hypergravity' approaches may be important as a common therapeutic approach on Earth and in space. Collectively, neurodegenerative diseases and space medicine may be linked to each other more strongly than previously thought.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8h/day, 5days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD.

Interleukin-1β (IL-1β) is a potent proinflammatory cytokine that is mainly produced by microglia in the central nervous system. It is considered to act as a key mediator of inflammatory processes not only in physiological conditions, but also during various pathological conditions, such as infection, injury, ischemia, and neurodegeneration. The mechanism through which such a leaderless protein is transferred from the cytoplasm to the extracellular space is an important unresolved issue in the study of IL-1β biology. Emerging evidence suggests that autophagy plays an important role in the unconventional secretion of IL-1β. Autophagy might negatively regulate IL-1β expression by lysosomal degradation, while mature IL-1β could be secreted by an autophagy-based Golgi reassembly stacking protein (GRASP)-dependent secretory pathway. We also found that activation of the P2X7 receptor (P2X7R), an ATP-gated cation channel, plays a critical role in the regulation of basal autophagy flux as well as the maturation and unconventional secretion of IL-1β in microglial cells. Taken together, better understanding of the role of the autophagy-lysosomal pathway in the maturation and secretion of IL-1β in microglia might provide a new strategy for targeting neuroinflammation in various pathological conditions.

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.

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 inα-synuclein (αS) transgenic and related model mice. In the majority ofαS transgenic mice, astrogliosis was observed concomitantly with accumulation ofαS 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 inαS 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.

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 β-synuclein. P123H β-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 β-synuclein tg mice, P123H β-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 β-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.

Gangliosides are sialic acid-containing glycolipids that are mainly localized in the outer leaflet of the plasma membrane of vertebrate cells and are involved in diverse physiological functions such as cell growth, differentiation, and cell-cell recognition(Hakomori, 1990). In the nervous system, gangliosides are highly expressed in neurons and are implicated in neurite outgrowth, synaptogenesis, and modulation of synaptic transmission(Posse de Chaves and Sipione, 2010). In this context, gangliosides have been proposed to act as coreceptors for growth factors (e.g. fibroblast growth factor) and neurotransmitters (e.g. serotonin)(Posse de Chaves and Sipione, 2010). Gangliosides are also localized in some glial cells in both gray and white matter, thereby affecting myelin sheath stability through association with myelin-associated glycoprotein(Schnaar, 2010). There is immense large body of knowledge on the biosynthesis and catabolism of gangliosides. In brief, gangliosides are synthesized by sequential addition of single sugars catalyzed by multiple glycosyltransferases (Fig. 1). The profiles of ganglioside components in neurons and glia are developmently regulated(Yamamoto et al., 1996; Yu et al., 2009). For instance, the dominant pathway in neurons during the neonate stage is pathway “a”, which starts from GM3 and leads to GT1a via GM1 and GD1a. In adult human brain, four gangliosides (GM1, GD1a, GD1b and GT1b) are mainly produced, and these make up the majority (> 66 %) of gangliosides in the brain(Ando et al., 1978). It is also believed that each ganglioside has a specific function in the brain and is not merely an intermediate metabolite in the synthesis of more prevalent gangliosides(Yamamoto et al., 1996; Yu et al., 2009). Gangliosides are in turn degraded by various lysosomal hydrolases with the aid of sphingolipid activator proteins. If a specific hydrolase required for this process is partially or totally missing due to a genetic deficit, gangliosides accumulate in the lysosomes and result in lysosomal dysfunction, which manifests as a lysosomal storage diseases (LSD)(Jalanko and Braulke, 2009; Vitner et al., 2010). Furthermore, it has been shown that gangliosides are secondarily upregulated in many other sphingolipidoses(Vitner et al.

In previous studies, we demonstrated that acute stress induces microglial activation, without inducing any inflammatory responses; however, the effect of acute stress on astroglia, another glial cell subtype in the brain, remains to be elucidated. We determined the effect of acute stress on astroglia, particularly in terms of morphological changes and inflammatory properties. In contrast to microglia, the morphology of astroglia was not altered following a 2-h period of acute stress. Interestingly, the number of astroglia immunoreactive to interleukin 1 beta (IL-1β) significantly increased in several brain regions including the hippocampus, hypothalamus, amygdala, and periaqueductal gray following the acute stress. Confocal microscopy revealed that IL-1β is exclusively co-localized in astroglia, and not in neurons or microglia. The present study demonstrates that exposing rats to acute stress increases IL-1β immunoreactivity in astroglia in specific regions of the brain, and the mechanism of astroglial response to acute stress clearly differs from that of microglial response. Thus, astroglia may play important roles in neuroimmunomodulation through IL-1β during times of acute stress.

The potent pro-inflammatory cytokine, interleukin-1β (IL-1β), is synthesized as an inactive 33-kDa precursor (pro-IL-1β) and is processed by caspase 1 into the bioactive 17-kDa mature form. The P2X7 receptor, an ATP-gated cation channel, plays an essential role in caspase 1 activation, production and release of mature bioactive 17-kDa form. We recently reported ATP induces the release of an unconventional 20-kDa form of IL-1β (p20-IL-1β) from lipopolysaccharide-primed microglial cells. Emerging evidence suggests physiological relevance for p20-IL-1β; however, the underlying mechanisms for its production and release remain unknown. Here, we investigated the pathways involved in the ATP-induced production of p20-IL-1β using lipopolysaccharide-primed mouse microglial cells. The activation of P2X7 receptor by ATP triggered p20-IL-1β production under acidic extracellular conditions. ATP-induced p20-IL-1β production was blocked by pepstatin A, a potent inhibitor of the lysosomal protease, cathepsin D. The removal of extracellular Ca(2+) inhibited the p20-IL-1β production as well as ATP-induced cathepsin D release via lysosome exocytosis. The acidic extracellular pH also facilitated the dilatation of membrane pore after ATP stimulation. Since facilitation of pore dilatation results in cytolysis accompanied with cytoplasmic pro-IL-1β leakage, our data suggest the leaked pro-IL-1β is processed into p20-IL-1β by cathepsin D released after ATP stimulation under acidic extracellular conditions.

Recent advances have been made in defining the genetic and molecular basis of dementia with Lewy bodies (DLBs) and related neurodegenerative disorders such as Parkinson's disease (PD) and Parkinson's disease dementia (PDD) which comprise the spectrum of “Lewy body disorders” (LBDs). The genetic alterations and underlying disease mechanisms in the LBD overlap substantially, suggesting common disease mechanisms. As with the other neurodegenerative dementias, early diagnosis in LBD or even identification prior to symptom onset is key to developing effective therapeutic strategies, but this is dependent upon the development of robust, specific, and sensitive biomarkers as diagnostic tools and therapeutic endpoints. Recently identified mutations in the synucleins and other relevant genes in PD and DLB as well as related biomolecular pathways suggest candidate markers from biological fluids and imaging modalities that reflect the underlying disease mechanisms. In this context, several promising biomarkers for the LBD have already been identified and examined, while other intriguing possible candidates have recently emerged. Challenges remain in defining their correlation with pathological processes and their ability to detect DLB and related disorders, and perhaps a combined array of biomarkers may be needed to distinguish various LBDs.

The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies., Little is known about β-synuclein mutations in neurological disease. In this article, the authors demonstrate that mice with a mutation in β-synuclein show progressive neurodegenerative disease and suggest that this mutation can enhance the brain defects caused by α-synuclein mutations in mice.

A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer's disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood-brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.

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.

Gangliosides are abundantly expressed in the nervous system, and deregulated expression or activity of gangliosides is associated with the progression of various disorders, including lysosomal storage diseases, Guillain-Barre syndrome and Alzheimer disease. By contrast, previous studies show that GM1 ganglioside may act in a protective manner in the drug (e.g., MPTP and 6-OHDA)-induced Parkinsonian models, although the precise mechanisms have not been well addressed. In our recent publication, dementia with Lewy bodies (DLB)-linked neuroblastoma cells were treated with D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthetase. These PDMP-treated cells develop lysosomal diseases characterized by reduced lysosomal activity, enhanced lysosomal permeability and cytotoxicity. Furthermore, PDMP-mediated inhibition of autophagy-lysosomal pathway result in both accumulation of alpha-synuclein and mutant beta-synuclein. Finally, these phenotypes are reversed by ganglioside treatment. Taken together, our results suggest that endogenous gangliosides may play a protective role against the lysosomal pathology of synucleinopathies.

Activins, TGF-beta superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin beta subunit genes, betaC and betaE, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin betaE 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.

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 αS- and 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 αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that is predominantly localized in the cytoplasm. However, recent studies have suggested that GAPDH is released by various cells and that extracellular GAPDH is involved in the regulation of neuritogenesis in neuronal cells. It has also been reported that GAPDH is expressed on the surfaces of macrophages and functions as a transferrin receptor. However, since GAPDH is a leaderless protein the mechanisms by which it reaches the extracellular environment remain unclear. Here, we examined the role of P2X7 receptor (P2X7R), an ATP-gated cation channel, in the unconventional release of GAPDH from microglial cells, the resident macrophages in the brain. The activation of P2X7R by ATP triggered GAPDH release from lipopolysaccharide (LPS)-primed microglial cells. ATP-induced microvesicle formation, exosome release, and K+ efflux followed by caspase-1 activation are likely involved in the GAPDH release, but ATP-induced dilatation of membrane pores and lysosome exocytosis are not. It was also demonstrated that exogenous GAPDH facilitated LPS-induced phosphorylation of p38 MAP kinase in microglial cells. These findings suggest that P2X7R plays an important role in the unconventional release of GAPDH from microglial cells, and the GAPDH released into the extracellular space might be involved in the regulation of the neuroinflammatory response in the brain.