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Sweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis
Mariko Noda,Akio Suzumura
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/891087
Abstract: Microglia are multifunctional immune cells in the central nervous system (CNS). In the neurodegenerative diseases such as Alzheimer's disease (AD), accumulation of glial cells, gliosis, occurs in the lesions. The role of accumulated microglia in the pathophysiology of AD is still controversial. When neuronal damage occurs, microglia exert diversified functions, including migration, phagocytosis, and production of various cytokines and chemokines. Among these, microglial phagocytosis of unwanted neuronal debris is critical to maintain the healthy neuronal networks. Microglia express many surface receptors implicated in phagocytosis. It has been suggested that the lack of microglial phagocytosis worsens pathology of AD and induces memory impairment. The present paper summarizes recent evidences on implication of microglial chemotaxis and phagocytosis in AD pathology and discusses the mechanisms related to chemotaxis toward injured neurons and phagocytosis of unnecessary debris. 1. Introduction Microglia are macrophage-like resident immune cells in the central nervous system (CNS) and possess both neurotoxic and neuroprotective function. Microglia accumulate in the lesions of a variety of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis, and are thought to play both toxic and protective functions for neuronal survival [1]. Microglia are considered to be a first line defense and respond quickly to various stimuli. When activated, microglia undergo morphological changes to ameboid, proliferate, migrate toward injured areas, and release many soluble factors and phagocytosis of foreign substances or unwanted self-debris. Appropriate migration of microglia to damaged area is controlled by chemokines and nucleotide ATP [2, 3]. Phagocytosis seems to be important to prevent the senile plaque expansion in AD by removing amyloid β (Aβ) deposit [4]. Microglia not only engulf the Aβ protein but also phagocytose apoptotic cells and degenerated neuronal debris. Phagocytosis of apoptotic or degenerated neuronal debris is crucial to reduce inflammation and maintain healthy neuronal networks. Another type of phagocytosis, phagocytosis with inflammation, occurs in chronic inflammatory-related neurodegenerative disorders including Alzheimer disease [5–7]. Degenerated neurons releases several signaling molecules, including nucleotides, cytokines, and chemokines, to recruit microglia and enhance their activities [8, 9]. The phenomenon are now termed as find-me, eat-me, and help-me signals. In this paper, we focused on
Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases
Hideyuki Takeuchi,Akio Suzumura
Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2014.00189
Abstract: Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g. minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity
Endong Li, Mariko Noda, Yukiko Doi, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-148
Abstract: The release of MFG-E8 from microglia treated with conditioned medium from neurons exposed to neurotoxic substances, glutamate or oligomeric amyloid β (oAβ) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8???induced microglial phagocytosis of oAβ were assessed by immunocytochemistry. The effects of MFG-E8 on the production of the anti-oxidative enzyme hemeoxygenase-1 (HO-1) were determined by ELISA and immunocytochemisty.MFG-E8 was induced in microglia treated with conditioned medium from neurons that had been exposed to neurotoxicants, glutamate or oAβ. MFG-E8 significantly attenuated oAβ-induced neuronal cell death in a primary neuron???microglia coculture system. Microglial phagocytosis of oAβ was accelerated by MFG-E8 treatment due to increased CD47 expression in the absence of neurotoxic molecule production, such as tumor necrosis factor-α, nitric oxide, and glutamate. MFG-E8???treated microglia induced nuclear factor E(2)???related factor 2 (Nrf2)???mediated HO-1 production, which also contributed to neuroprotection.These results suggest that microglia release MFG-E8 in response to signals from degenerated neurons and that MFG-E8 protects oAβ-induced neuronal cell death by promoting microglial phagocytic activity and activating the Nrf2-HO-1 pathway. Thus, MFG-E8 may have novel roles as a neuroprotectant in neurodegenerative conditions.
Fingolimod Phosphate Attenuates Oligomeric Amyloid β–Induced Neurotoxicity via Increased Brain-Derived Neurotrophic Factor Expression in Neurons
Yukiko Doi, Hideyuki Takeuchi, Hiroshi Horiuchi, Taketo Hanyu, Jun Kawanokuchi, Shijie Jin, Bijay Parajuli, Yoshifumi Sonobe, Tetsuya Mizuno, Akio Suzumura
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061988
Abstract: The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.
Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)
Maria Burkovetskaya, Nikolay Karpuk, Juan Xiong, Megan Bosch, Michael D. Boska, Hideyuki Takeuchi, Akio Suzumura, Tammy Kielian
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095023
Abstract: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.
Transmedullary Decompression for Humeral Diaphysis Solitary Bone Cysts  [PDF]
Akio Sakamoto
Open Journal of Orthopedics (OJO) , 2013, DOI: 10.4236/ojo.2013.32015

Solitary bone cysts are benign, fluid-filled cavities that most often occur in childhood. Several minimally invasive decompression methods have been proposed; however, performing a surgical procedure through the thinned overlying cortex raises the risk of pathological fracture and neurovascular damage, especially in lesions located in the bone diaphysis. We describe a new technique that circumvents these problems: tunneling through the normal cortex and medullary space with a flexible reamer, placing a retrograde medullary nail for cyst decompression.

A Simple and Fast Separation Method of Fe Employing Extraction Resin for Isotope Ratio Determination by Multicollector ICP-MS  [PDF]
Akio Makishima
International Journal of Analytical Mass Spectrometry and Chromatography (IJAMSC) , 2013, DOI: 10.4236/ijamsc.2013.12012

A new, simple and fast separation method for Fe using an extraction chromatographic resin, Aliquat 336 (commercially available as TEVA resin) has been developed. A one milliliter column containing 0.33 mL TEVA resin on 0.67 mL CG-71C was used.Iron was adsorbed with 6mol·L-1 HCl + H2O2 on TEVA resin, and recovered with 2 mol·L-1HNO3. The recovery yield and total blank were 93.5 ± 6.5% and 6 ng, respectively. Theseparation method is simple, and takes < 2 hours. For evaluation of the Fe separation, Fe isotope ratios were measured by a double-spike method employing multicollector inductively coupled plasma source mass spectrometry (MC-ICP-MS) with repeatability of 0.06‰ (SD) for the standard solution and ~0.05‰ for the silicate samples. Therefore, the column chemistry developed in this study is a viable option for Fe isotope ratio measurement by MC-ICP-MS.

Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
Hideyuki Takeuchi, Hiroyuki Mizoguchi, Yukiko Doi, Shijie Jin, Mariko Noda, Jianfeng Liang, Hua Li, Yan Zhou, Rarami Mori, Satoko Yasuoka, Endong Li, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Jun Sato, Koji Yamanaka, Gen Sobue, Tetsuya Mizuno, Akio Suzumura
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021108
Abstract: Background Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. Methods and Findings In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. Conclusions Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
Ablation of Keratan Sulfate Accelerates Early Phase Pathogenesis of ALS
Kenichi Hirano, Tomohiro Ohgomori, Kazuyoshi Kobayashi, Fumiaki Tanaka, Tomohiro Matsumoto, Takamitsu Natori, Yukihiro Matsuyama, Kenji Uchimura, Kazuma Sakamoto, Hideyuki Takeuchi, Akihiro Hirakawa, Akio Suzumura, Gen Sobue, Naoki Ishiguro, Shiro Imagama, Kenji Kadomatsu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066969
Abstract: Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1G93A mice and GlcNAc6ST-1?/? mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1G93AGlcNAc6ST-1?/? mice exhibited a significantly shorter lifespan than SOD1G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1G93A mice, while this enhancement was attenuated in SOD1G93AGlcNAc6ST-1?/? mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1G93AGlcNAc6ST-1?/? mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.
Influence of Pressure on Germination of Garden Cress, Leaf Mustard, and Radish Seeds at Various Temperatures  [PDF]
Akio Shimizu, Jun Kumakura
American Journal of Plant Sciences (AJPS) , 2011, DOI: 10.4236/ajps.2011.23050
Abstract: The effects of hydrostatic pressure (0.1 - 400 MPa) and temperature (4°C, 25°C, and 35°C) on the germination of three types of seeds (garden cress, leaf mustard, and radish) were studied. The normal germination rate of the three types of seeds was decreased at high hydrostatic pressure, and germination time tended to be delayed. Pressure and temperature had two types of effects on seed germination. Germination of garden cress and leaf mustard seeds was more resistant to pressure at lower temperature. Conversely, germination of radish seeds was most pressure-sensitive at low temperature, and germination drastically decreased with treatment at 50 MPa and 4°C. Generally, pressure and temperature effects on protein structure and enzyme activity have been classified into two types, “hillside”-like (pressurization decreases the stable temperature range) and “tongue”-like (stabilizing effect of moderate pressure against heat denaturation). Therefore, the type of temperature-pressure effects on germination of garden cress and leaf mustard seeds is classified as “hillside”-like and that of radish seeds is classified as “tongue”-like, similarly to the generally observed effects on protein denaturation.
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