シンポジウム
07 神経炎症と認知症・神経変性疾患：脳・全身連関の理解から治療へ
07 Neuroinflammation in dementia and neurodegenerative diseases: understanding brain-systemic interaction for therapeutics
座長：山中 宏二（名古屋大学 環境医学研究所）・富田 泰輔（東京大学薬学系研究科） |
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| 2022年7月2日 9:00～9:24 沖縄コンベンションセンター 会議場A1 第2会場
3S02m-01
筋萎縮性側索硬化症モデルマウスにおけるミクログリアの不均一性と機能変化
Alterations of microglial heterogeneity and functions in amyotrophic lateral sclerosis model mice
*小峯 起(1)、日野原 邦彦(2,3,4)、荻 朋男(5)、嶋田 繭子(5)、紅 朋浩(6,4)、大沼 周平(1)、山中 宏二(1)
1. 名古屋大学環境医学研究所病態神経科学、2. 名古屋大学医学系研究科免疫学、3. 名古屋大学高等研究院、4. 名古屋大学5D細胞ダイナミクス研究センター、5. 名古屋大学環境医学研究所発生遺伝、6. 名古屋大学医学系研究科神経疾患・腫瘍分子医学研究センター
*Okiru Komine(1), Kunihiko Hinohara(2,3,4), Tomoo Ogi(5), Mayuko Shimada(5), Tomohiro Akashi(6,4), Syuhei Ohnuma(1), Koji Yamanaka(1)
1. Dept of Neurosci & Pathobiol, Res Inst Enviro Med, Nagoya Univ, 2. Dept of Immunol, Nagoya Univ Grad Sch Med, 3. Inst for Adv Res, Nagoya Univ, 4. Cent for 5D Cell Dyna, Nagoya Univ, 5. Dept of Genetics, Res Inst Enviro Med, Nagoya Univ, 6. Cent for Neurol Dis & Cancer, Nagoya Univ Grad Sch Med
Keyword: ALS, Microglia, scRNA-seq
Recent advance in single-cell analyses including a single-cell RNA sequencing (scRNA-seq) revealed that microglia are comprised of a heterogenous population in various regions of central nervous system and maintain a homeostasis under healthy condition. In contrast, under disease condition, such as amyotrophic lateral sclerosis (ALS), it was recently reported that microglia lose homeostatic functions following activation, and then convert into distinct subpopulation referred to as disease-associated microglia (DAM) expressing characteristic gene subsets in ALS model mice (SOD1G93A (G93A) mice). However, the role of DAM in ALS pathology remains unclear. Furthermore, previous studies indicate that G93A mice with different genetic backgrounds exhibit different disease progressions and survival times. However, whether genetic difference affects microglial heterogeneity and functions remains to be elucidated. Therefore, to clarify the impact of genetic difference on microglial heterogeneity and functions in ALS pathogenesis, we generated two strains of G93A mice (G93A(B6), G93A(Balb)) with the genetic backgrounds of C57BL/6 or BALB/c and performed scRNA-seq in these spinal cords and both wild-type ones. Clustering analyses revealed that microglial population was separated into two clusters expressing homeostasis-related genes (cluster 1) or DAM-related genes (cluster 2) in all genotypes. Although almost all microglia belonged to cluster 1 and the rest of microglia belonged to cluster 2 in both wild-type mice, almost all G93A(B6) microglia converted from cluster 1 into cluster 2 and increased in number of total microglia, whereas G93A(Balb) microglia failed to convert into cluster 2 and significantly decreased in number of total microglia. To examine the influence of these alterations in microglia heterogeneity on the pathogenesis, we next performed survival analyses. We found that G93A(Balb) mice exhibited the shorter survival times with accelerated disease progression. Our subsequent gene expression analyses and immunohistological stainings revealed decreased expressions of neurotrophic factor, IGF-1 and microglia growth factor, M-CSF in G93A(Balb) microglia. In addition, we also confirmed the decreased in number of microglia in the G93A(Balb) spinal cords by using FACS. These data suggest that genetic difference affects to not only microglial heterogeneity but also ALS pathogenesis by changing the microglia growth and neuroprotective microglial responses. The role of each microglia cluster in ALS pathogenesis will be discussed. | | 2022年7月2日 9:24～9:48 沖縄コンベンションセンター 会議場A1 第2会場
3S02m-02
ミクログリア炎症機構とアルツハイマー病病態
Roles of microglial inflammatory platforms in AD pathogenesis
*斉藤 貴志(1)
1. 名古屋市立大学大学院医学研究科
*Takashi Saito(1)
1. Nagoya City University
Keyword: Alzheimer's disease, neuroinflammation, microglia, inflammasome
Alzheimer’s disease (AD) is the most common type of neurocognitive disorder, and its socioeconomics demand that it be overcome as soon as possible. However, the pathogenesis of the disease remains unclear. In the process leading up to the final stage of AD, the neuronal dysfunction has come to be viewed not only as a failure of the neurons themselves, but also as dysregulations of the cellular environment surrounding the neurons. In other words, glial cells are thought to play an important role in the pathogenesis of AD. The response of glial cells to amyloid plaques and neurofibrillary tangles, the two major pathologies observed in AD, is also regarded as neuroinflammation and is tightly regulated like the peripheral immune response. Using App knockin mice as a model of AD, we are focusing on the response mechanism of glial cells to amyloidosis. Recently, we have analyzed the role of inflammatory platforms, e.g. the NF-kB signaling pathway and inflammasomes, in amyloidosis. Thus, we analyzed amyloid plaque formation and glial pathologies by deleting NF-kB signaling pathway and inflammasome specifically in microglia. Interestingly, in contrast to previous reports, accelerating the microglial inflammatory response did not promote amyloid pathology. Furthermore, suppression of the microglial inflammatory response did not inhibit the formation of amyloid pathology. In this symposium, we would like to introduce these results and discuss the prospects of glial cell research in AD pathogenesis. | | 2022年7月2日 9:48～10:12 沖縄コンベンションセンター 会議場A1 第2会場
3S02m-03
認知症における脳エネルギー代謝とグリア細胞
Brain energy metabolism and glial cells in dementia
*高堂 裕平(1)
1. 量子科学技術研究開発機構
*Yuhei Takado Takado(1)
1. National Institutes for Quantum Science and Technology
Keyword: Alzheimer's disease, Brain energy metabolism, Astrocyte, Magnetic Resonance Spectroscopy
Decreased glucose uptake in the brain of Alzheimer’s disease (AD) patients has been demonstrated by 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) in clinical studies and these findings are interpreted as a sign of neurodegeneration. However, it has been reported that the uptake of FDG is also affected by the activity of astrocytes and microglia, and the mechanism of impaired glucose metabolism in the brain of AD patients is not fully understood. To clarify the mechanism of glucose metabolism impairment in AD, we performed magnetic resonance spectroscopy (MRS) in AD patients and healthy subjects. We measured brain metabolites using MRS in the posterior cingulate gyrus region, where FDG uptake is decreased by PET, in AD. The MRS results showed increased lactate, glucose, and myoinositol, an astrocytic marker, concentrations in AD patients compared to healthy subjects. Moreover, lactate levels are positively correlated with myoinositol levels in the posterior cingulate gyrus region of AD patients. While glucose is metabolized to lactate in astrocytes and lactate is suggested to be a fuel source for neurons, the glucose metabolism impairment indicated by the increase in lactate and glucose levels was suggested to be associated with altered astrocyte function as was shown by increased myoinositol. Next, to clarify how amyloid and tau are involved in astrocyte function changes in AD patients, we performed MRS using mouse models with AD-like accumulation of amyloid or tau. While the amyloid-accumulated mouse model showed a more pronounced increase in lactate and myoinositol, the changes were not evident in the mouse model of tau accumulation in neurons, suggesting the more relevant association between astrocyte dysfunction and amyloid than tau in AD pathology. On the other hand, the clinical MRS results showed increased lactate and myoinositol concentrations in the brain of progressive supranuclear palsy patients, a tauopathy characterized by tau accumulation in astrocytes, indicating that internal tau accumulation could be a trigger for functional changes of astrocyte. Evaluation of MRS in humans and mice suggested that glial cells, especially astrocytes, contribute to abnormal glucose metabolism in dementia. In the future, we will investigate the mechanism of astrocyte dysfunction underlying abnormal energy metabolism to clarify the mechanism of dementia onset and to develop diagnostic and therapeutic methods. | | 2022年7月2日 10:12～10:36 沖縄コンベンションセンター 会議場A1 第2会場
3S02m-04
アルツハイマー病治療を志向したアミロイド光酸素化技術の開発
Photooxygenation as a new therapeutic strategy against Alzheimer disease
*堀 由起子(1)
1. 東京大学大学院薬学系研究科
*Yukiko Hori(1)
1. Grad Sch Pharm Sci, Univ of Tokyo, Tokyo, Japan
Keyword: amyloid, Alzheimer disease
Alzheimer disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, as senile plaque, in the brains of patients. For AD therapy, the immunotherapies using anti-Aβ antibodies have been highlighted as the promising approach by enhanced microglial clearance of Aβ. However, the development of an alternative strategy to facilitate the clearance of brain amyloids is also needed, as the efficiency of the antibody delivery into the brain is limited.
For the therapeutic strategy, we have developed the artificial photooxygenation system using photocatalysts that selectively bind to cross-β sheet structure, which is the characteristic structure of the amyloid fibrils. These catalysts are activated by the light irradiation only when the compounds bind to the cross-β sheet structure. The activated catalysts generate the singlet oxygen, resulting in the oxygenation of the amyloid aggregates nearby the compounds. We showed that the photooxygenation of synthetic aggregated Aβ using these catalysts attenuated the further aggregation potency, leading to lower the neurotoxicity of Aβ in vitro. To verify the effects of the photooxygenation on deposited Aβ in brain, we carried out the in vivo photo-oxygenation using AD model mice. We successfully photooxygenate the deposited Aβ in brain of living AD model mice, and found that the photooxygenation decreased the amount of Aβ in the brain. We also showed that the photooxygenated Aβ aggregates were cleared faster than that of non-modified Aβ aggregates in a microglia-dependent manner. These data suggest that the photo-oxygenation has a potential as novel useful strategy against AD, which is compatible with immunotherapy. We would like to elucidate the molecular mechanism of the photooxygenation to further improve this strategy for AD therapy. | | 2022年7月2日 10:36～11:00 沖縄コンベンションセンター 会議場A1 第2会場
3S02m-05
軸索初節の可塑性と神経変性・神経炎症
The plasticity of the axon initial segment in neurodegeneration and neuroinflammation
*桐生 寿美子(1)、木山 博資(1)
1. 名古屋大学大学院医学系研究科
*Sumiko Kiryu-Seo(1), Hiroshi Kiyama(1)
1. Grad Sch Med, Nagoya University, Aichi, Japan
Keyword: nerve degeneration, motor neuron, ATF3, mitochondria
Impairment of proteostasis is highly implicated in pathologically damaged neurons of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). In particular, motor neurons are susceptible to the proteasomal dysfunction. However, it is not clear how proteasome impact on stress resilience in damaged motor neurons. To address this issue, we have used motor nerve injury model as a simple and elegant experimental model to examine the stress resilient mechanism that is lacking in degenerative motor neurons. We have generated novel mice wherein genetic modification and mitochondrial labeling occur simultaneously in response to damage. These mice enable us to monitor the behavior of fluorescently-labeled mitochondria in damaged neurons in 3D and 2D manner. Mitochondria in mature neurons need to pass through a specialized compartment between the soma and axon called the axon initial segment (AIS) to deliver the energy into the axon. We have found that Ankyrin G, an organizer of the AIS, is a potential target of proteasome in damaged motor neurons. Upon injury, the motor neuron AIS is temporarily disassembled in a proteasome-dependent manner. The AIS dismantling in turn allows injury-induced mitochondrial influx into axons and satisfies the energy demand to promote axon regeneration. Inflammatory response may be involved in the regulation of the AIS dynamics because ultrastructural analysis showed that activated microglial cells in response to injury adhere directly to the AIS prior to the AIS disassembly. Injury-induced proteasome-deficient motor neurons fail to disassemble the AIS, thereby restricting the increased influx of mitochondria into axons. At this time point, these neurons initiate the transcriptional reprogramming for regeneration but thereafter exhibit ALS-like degeneration along with robust microglial activation. Intriguingly, vulnerable subtype of SOD1G93A ALS motor neurons also fail to disassemble the AIS although they initiate reprogramming response to pathological damage. Here we show that the AIS disassembly is a critical post-translational stress response for damaged motor neurons to supply enough energy into axons. The appropriate regulation of this system could be of a new therapeutic target in neurodegenerative diseases. | | | |
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