神経化学教育口演セッション (Neurochemistry Educational Oral Sessions)

神経化学教育口演セッション2 Cerebellum
O3-8-4-1 Arctic Amyloid βのCHRNA7受容体に対する作用検証 Arctic mutant Aβ; affects CHRNA7's functions ○キョウ曄¹, 朝日透^1,2, 澤村直哉² ○Ju Ye¹, Toru Asahi^1,2, Naoya Sawamura² 早大院・理工¹, 早大・ASMeW² Dept Sci & Eng, Wasade Univ, Tokyo¹, ASMeW, Waseda Univ.² The nicotinic acetylcholine receptors, key players in neuronal communication, convert neurotransmitter binding into membrane electrical depolarization. CHRNA7 is one type of the neuronal nicotinic acetylcholine receptors, which is thought to relate to Alzheimer's disease, because Aβ42 is reported binding to CHRNA7 protein with high affinity. Point mutations within the Aβ sequence that are associated with hereditary disease similar or identical to AD are clustered around the central hydrophobic core of Aβ. Therefore, we came up with the hypothesis about mutant Aβ modifies CHRNA7's function, which could relate to the Familial Alzheimer's Disease. We detected the in vitro binding ability of mutant Aβ with CHNRA7 by immunoprecipitation and found out that Arctic mutant Aβ specifically bound to CHRNA7. We also observed the aggregation of Arctic mutant Aβ with addition of CHRNA7 through transmission electron microscopy (TEM). CHRNA7 is the cholinergic receptor controlling cellular calcium ions (Ca²⁺) homeostasis and ERK1/2 protein is involved in CHRNA7 function. Thus, we detected whether Arctic Aβ could affect permeability to Ca²⁺ . As a result, we found out that Arctic Aβ could inhibit the CHRNA7 function via decrease in Ca²⁺ and inhibition of ERK1/2 activation.	O3-8-4-2 ニューロプシンによるErbB4 シグナリングの制御 Neuropsin-mediated regulation of ErbB4 signaling ○河田美穂¹, 石川保幸¹, 塩坂貞夫¹ ○Miho Kawata¹, Yasuyuki Ishikawa¹, Sadao Shiosaka¹ 奈良先端科学技術大学院大学・バイオサイエンス・神経機能科学¹ Laboratory of Functional Neuroscience, Graduate School of Biological Science, Nara Institute of Science and Technology, Nara, Japan¹ Neuropsin plays as an important modulator of the nervous system. Recent our studies have reported that neuropsin proteolytically removes proteoglycan binding domain of neuregulin-1 (NRG-1), a risk factor of schizophrenia, allows binding its specific receptor, ErbB4, and leads to upregulation of GABAergic signaling. Our in vitro study demonstrated that neuropsin produces three kinds of fragments, 32, 28, and 19Kd depending on the cleavage sites. However, it is still unclear what fragments produced by the neuropsin-dependent cleavage of NRG-1 is responsible for synaptic plasticity and how the cleaved fragment act in vivo. To analyze these issues, we generated antibodies recognizing each of neuropsin-specific cleavage sites of NRG-1. Antibodies successfully detected NRG-1 fragments with cleavage site specific manner without detecting full length NRG-1. In addition, to analyze these issues in vivo, we tried intraperitoneal injection of excite toxin, kainic acid to induce hyper active state of the brain and found that the drug induced significant elevation of neuropsin's protease activity and phosphorylated ErbB4.
O3-8-4-3 ALSマウスモデルにおけるコネキシン蛋白の神経病理学的検討 Connexin gap junction pathology in the SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS) ○真崎勝久¹, 崔訳文¹, 山崎亮¹, 林信太郎¹, 長柄祐子¹, 河村真実¹, 佐藤眞也¹, 大八木保政¹, 吉良潤一¹ ○Katsuhisa Masaki¹, Yiwen Cui¹, Ryo Yamasaki¹, Shintaro Hayashi¹, Yuko Nagara¹, Mami Kawamura¹, Shinya Sato¹, Yasumasa Ohyagi¹, Jun-ichi Kira¹ 九州大学大学院医学研究院神経内科学¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu university, Fukuoka, Japan¹ Background: Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model. Connexins (Cxs) form gap junctions (GJs) between astrocytes, or between astrocytes and oligodendrocytes. The status of Cxs has never been investigated in ALS. Objective: The present study aimed to evaluate the alterations of astrocytic and oligodendrocytic Cxs in the mSOD1-transgenic (mSOD1-Tg) mice at the presymptomatic stage (12 weeks of age), the disease progression stage (18 weeks of age) and end stage (20 weeks of age) and in their non-transgenic (N-Tg) mice at the same ages. Method: We pathologically evaluated the temporal changes of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 relative to AQP4, GFAP, EAAT2, MOG, and Nogo-A immunoreactivities, and observed neuronal loss and microglial response by NeuN and Iba-1 immunostainings on disease progression. We also performed the quantitative immunoblot. Result: mSOD-Tg mice showed neuronal loss at anterior horn of lumbar spinal cord and increased numbers of recruited activated microglia at disease progression stage. Expression patterns of Cxs were not different between mSOD-Tg and N-Tg mice at presymptomatic stage, while GFAP, Cx43 and AQP4 were up-regulated in the gray matter of mSOD-Tg mice at the disease progression stage and end stage. By contrast, immunoreactivities for EAAT2 and Cx30 were decreased in the gray matter of some mSOD1-Tg mice at the disease progression stage and end stage. Cx47 and Cx32 expressions were markedly diminished in the Nogo-A-positive oligodendrocyte somatic membrane of the gray matter of mSOD1-Tg mice. Quantitative immunoblot revealed significant reduction of Cx47 and Cx32 protein levels in mSOD1-Tg mice at the end stage. Conclusion: Our findings indicate that oligodendrocyte and astrocyte GJs are affected in the gray matter of mSOD1-Tg mice, where disruption of GJs may contribute to exaggerated neuronal death.	O3-8-4-4 FABP3はドパミン神経細胞における α-synucleinの蓄積を増悪する FABP3 aggravates α-synuclein accumulation in the dopaminergic neurons ○矢吹悌¹, 塩田倫史¹, 小林由佳¹, 大和田祐二², 福永浩司¹ ○Yasushi Yabuki¹, Norifumi Shioda¹, Yuka Kobayashi¹, Yuji Owada², Kohji Fukunaga¹ 東北大学大学院薬学研究科薬理学分野¹, 山口大学大学院医学系研究科器官解剖学分野² Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan¹, Department of Organ Anatomy, Yamaguchi University Graduate school of Medicine, Ube, Japan² Accumulation of α-synuclein in the dopaminergic neurons is one of pathogenesis of Parkinson's disease, and its formation is partly regulated by long-chain polyunsaturated fatty acids (LCPUFAs) such as arachidonic acid (AA). Fatty acid-binding protein 3 (FABP3, H-FABP) is critical for AA uptake and metabolism in the brain. We previously demonstrated that FABP3 is highly expressed in the dopaminergic neurons, especially in the substantia nigra pars compacta (SNpc) (Shioda et al., J Neurosci, 2010;30:3146-55). However, the function of FABP3 in the dopaminergic neurons remains unclear. We found that the dopaminergic neurons in FABP3 null mice were resistant to MPTP-induced neurodegeneration, thereby improving motor deficits. Unexpectedly, there was no significant difference in MPP+-induced prostaglandin E2 (PGE2) production between wild-type and FABP3 null mice in co-cultured mesencephalic neurons with microglia. Interestingly, MPTP-induced α-synuclein accumulation in SNpc was attenuated in FABP3 null mice compared with wild-type mice. In addition, we confirmed that α-synuclein oligomerization was promoted by AA treatment in FABP3-overexpressed PC12 cells compared with mock cells. Taken together, the formation of oligomers of α-synuclein is partly regulated by FABP3 with AA in the dopaminergic neurons. Therefore, FABP3 null mice reveal the resistance for MPTP-induced neurodegeneration of the dopaminergic neurons.

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