公募シンポジウム２：タンパク凝集とグリア制御破綻による神経疾患の病態
Symposium2 : Dysregulation of neuro-glial cells in neurological disorder |
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| 2020/9/10 10:50～11:10 Zoom A
SY2-01
アルツハイマー病の疾患修飾療法のターゲットとしてのプロトフィブリル
Protofibrils as targets for disease-modifying therapy of Alzheimer's disease
*小野 賢二郎1
1. 昭和大学医学部 内科学講座 脳神経内科学部門
*Kenjiro Ono1
1. Division of Neurology, Department of Medicine, Showa University School of Medicine
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and is characterized by specific pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (amyloid hypothesis). Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these Aβ species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of Aβ and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent basic and human studies using synthetic Aβ peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of Aβ, particularly Aβ protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of Aβ1-42 disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.
| | 2020/9/10 11:10～11:30 Zoom A
SY2-02
マイクログリア/マクロファージの調節を介した骨髄由来幹/前駆細胞の神経保護能
Neuroprotective potency of bone marrow derived mesenchymal stem/progenitor cells by modulating of microglial/macrophages.
*大滝 博和1
1. 昭和大学医学部 顕微解剖
*Hirokazu Ohtaki1
1. Dept. Anat. Showa Univ. Sch. Med.
Bone marrow-derived mesenchymal stem/stromal cells (MSCs) are multipotent tissue stem cells that have shown promise in facilitating suppression and/or recovery after neuronal injury. We have examined that xenografting human MSCs (hMSCs) into mice subjected to spinal cord injury and brain ischemia protected against short-term neurological deficits and damage; however, the levels of the grafted hMSCs decreased significantly within the first week. Further experiments indicated that hMSCs might communicate with recipient tissues and thereby convert the phenotypic polarization of host microglia/macrophages (MG/MΦ) to an alternatively activated phenotype (AAM), which is known to promote tissue repair and regeneration after injury. However, it was unclear how hMSCs modulated the MG/MΦ during injury. We have recently revealed a communication between hMSCs and MG/MΦ through chemokines. In this symposium, we introduce role of hMSCs and the communication with MG/MΦ.
| | 2020/9/10 11:30～11:50 Zoom A
SY2-03
網膜神経変性におけるグリア小胞体ストレス応答の役割
The role of glial endoplasmic reticulum stress response in retinal neurodegeneration
*宝田 美佳1、郡山 恵樹2、堀 修1
1. 金沢大学、2. 鈴鹿医療科学大学
*Mika Takarada-Iemata1, Yoshiki Koriyama2, Osamu Hori1
1. Kanazawa Univ., 2. Suzuka Univ. Med. Sci.
The endoplasmic reticulum (ER) is the major organelle for protein synthesis and maturation, and disturbance of ER protein homeostasis leads to impairment of cellular function. Protein misfolding in the ER induces unfolded protein response (UPR) which coordinates protein homeostasis through the regulation of protein quality, synthesis and degradation. Accumulating evidence suggests a crucial role of UPR in neuropathological conditions such as brain ischemia, trauma and neurodegenerative disorders. However, it is not fully understood how UPR affect to the neuro-glia interaction in neurodegenerative condition. We have reported the role of UPR in glial activation in the mouse model of brain stroke, Parkinson's disease and multiple sclerosis. In this study, we investigated the relevance of ATF6α, a key transducer of the UPR signaling, in optic nerve crush injury (ONI), a simple neurodegeneration model which also used as a mouse model of glaucoma. Genetic deletion of ATF6α exacerbated neurodegeneration of retinal ganglion cell (RGC) after ONI. ATF6α knockout mice showed lower expressions of reactive glial markers for Müller glia and astrocytes such as GFAP and phosphorylated STAT3, and also showed lower expression of neurotrophic factor after ONI. ER stress exposure to cultured retinal glia also resulted in reduced expression of glial markers and neurotrophic factor, and those reductions were ameliorated by chemical chaperone treatment. Glia specific ATF6α knockout also showed reduced glial activation and lower RGC survival after ONI. These results suggest that ATF6α may play important roles in the survival of RGCs through the promotion of glial neuroprotective function in the process of neurodegeneration, including glaucoma.
| | 2020/9/10 11:50～12:10 Zoom A
SY2-04
脳梗塞後遺症の機能回復を目指した低酸素低糖刺激ミクログリア治療
Treatment for functional recovery after stroke using microglia preconditioned by oxygen-glucose deprivation
*下畑 享良1
1. 岐阜大学大学院医学系研究科 脳神経内科学分野
*Takayoshi Shimohata1
1. Department of Neurology, Gifu University Graduate School of Medicine
We demonstrated that administration of primary microglia or peripheral blood mononuclear cells (PBMCs) preconditioned by optimal oxygen-glucose deprivation (OGD) prompted functional recovery after focal cerebral ischemia by marked secretion of remodeling factors. In this symposium, I will discuss the mechanism and possible therapeutic application of this novel cell therapies.
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