「ミクログリアまつり」シンポジウム３
"Microglia Matsuri" Symposium 3 |
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| 2020/9/12 14:50～15:15 Zoom A
MM3-01
神経成分の脳外への排出を司る2つの経路の発見
Discoveries of two distinct pathways responsible for the clearance of neuronal components from the brain
*樋口 真人1、田桑 弘之1、高橋 真奈美1
1. 量子科学技術研究開発機構
*Makoto Higuchi1, Hiroyuki Takuwa1, Manami Takahashi1
1. National Institutes for Quantum and Radiological Science and Technology
The deposition of misfolded protein species exemplified by aberrant conformers of tau and alpha-synuclein is a pathological hallmark of diverse neurodegenerative disorders. These neurotoxic components are implied to be homeostatically eliminated from the brain, while cellular pathways responsible for this clearance mechanism remain elusive. We have longitudinally tracked fibrillary assemblies of misfolded tau and alpha-synuclein in the brains of living mouse models by intravital two-photon laser microscopy and mesoscopy following systemic administration of an imaging agent for these aggregates, along with expressions of fluorescence proteins in specific cell types. In normal mice, protein fibrils inoculated into the neocortex were taken up by perivascular astrocytes and were then transported to the brain surface, presumably via periarteriolar macrophages. Subsequently, dural and subarachnoidal macrophages captured this protein garbage and excreted it to subarachnoidal veins as extracellular vesicles. In transgenic mice modeling neurodegenerative tau pathologies, neurons bearing tau fibrils underwent primary phagocytosis by rod-shaped microglia, followed by transports of vesicles containing neuronal remnants to the brain surface through vertical processes of these microglial cells. Neuronal components were then processed by macrophages and were released to the bloodstream similar to inoculated protein filaments. This aggressive elimination of viable neurons led to massive brain atrophy in a progressive manner. Our findings indicate two distinct pathways composed of glial cells and border-associated macrophages responsible for the homeostatic clearance of misfolded proteins and the detrimental removal of neurons from the brain.
| | 2020/9/12 15:15～15:40 Zoom A
MM3-02
アルツハイマー病におけるミクログリア分子病態の解明
Understanding the molecular microglial pathology in Alzheimer disease
*富田 泰輔1
1. 東京大学大学院薬学系研究科 機能病態学教室
*Taisuke Tomita1
1. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Aggregated forms of the amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, which are pathological hallmarks in the brains of Alzheimer disease (AD) patients. Several lines of evidence suggest that accumulation of Aβ induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, facilitation of the clearance of aggregated Aβ and tau has been highlighted as a plausible therapeutic for AD. In addition, genetic studies in AD implicate the pathological roles of glial cells, such as astrocytes and microglia. Especially, recent researches highlight the importance of triggering receptor expressed on myeloid cells 2 (TREM2), which is specifically expressed in microglia in the central nervous system, in the pathological process of AD. TREM2 associated with DNAX activation protein of 12 kDa (DAP12) encoded by TYROBP gene to constitute a receptor/adaptor signaling complex. TREM/TYROBP signaling is negatively regulated by INPP5D, which is also a genetic risk factor for AD. Using in vitro and in vivo models, we found that TREM2/TYROBP/INPP5D signaling pathway is involved in the phagocytotic activity as well as the accumulation of microglia for aggregated Aβ. Intriguingly, exacerbated neuronal pathology in TYROBP KO mouse was not recovered in TYROBP/INPP5D double KO mouse, suggesting that the neuroprotective function of microglia is independent of INPP5D independent pathway. I will discuss these novel signaling pathways for the development of a novel therapeutic approach against AD.
| | 2020/9/12 15:40～16:05 Zoom A
MM3-03
コネキシン機能異常によるミクログリア異常活性化が多発性硬化症モデル動物に及ぼす影響の解明と治療応用
Microglial contribution in the development and maintenance of glial inflammation with connexin malfunction in the demyelinating lesion of multiple sclerosis model mice
*山崎 亮1
1. 九州大学大学院医学研究院 神経内科学
*Ryo Yamasaki1
1. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University
Connexins, which comprise gap junctions via homotypic/heterotypic oligomerization, act as channels to connect opposing cells, mainly in solid organs such as the skin, liver, heart, and central/peripheral nervous system. Connexins are synthesized and inserted into the cell membrane as hemichannels. Opening of hemichannels, which depends on the intra- or extracellular environment, allows various bioactive molecules to enter into or be released from the host cells. Recent pathological studies on human demyelinating diseases have revealed alterations of connexin expression patterns in demyelinating lesions. To elucidate the molecular mechanisms of connexins in the pathomechanisms of inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in connexin 30 (Cx30)-deficient mice, oligodendroglia-specific Cx47-ablated mice, and astroglia-specific Cx43-ablated mice. We found that both astroglial-Cx30-deficient mice and Cx43-ablated mice showed amelioration of the clinical course of EAE, while oligodendroglial-Cx47-ablated mice showed aggravation. These findings indicate the distinct role of connexins expressed in different cell types and the substantial contribution of connexin-mediated pathology to demyelinating disorders. The imbalance in connexin expression, which is caused by the inflammatory environment, results in an increase in hemichannels in glial cells. The release of pro-inflammatory molecules induced by the increase in hemichannels on activated glial cells is a crucial mechanism of demyelinating disorders.
| | 2020/9/12 16:05～16:30 Zoom A
MM3-04
一次性ミクログリア病の病態から考えるミクログリアを標的とした治療の可能性
Restoration of microglia may be a potential therapeutic approach: consideration from the pathogenesis of primary microgliopathy
*池内 健1
1. 新潟大学脳研究所 生命科学リソース研究センター
*Takeshi Ikeuchi1
1. Brain Research Institute, Niigata University
In the human brains, about 30% of microglia is replaced every year. Microglia play physiological roles including pruning of the synapse and myelin restoration. It is well-known that various neurological conditions are associated with the microglia dysfunction. The heterozygote mutations of CSF1R that is important for microglial differentiation and proliferation cause the white matter disease, called ALSP. The homozygous CSF1R mutation cause early-onset leukoencephalopathy. In brains of ALSP patients, the attenuation of the microglial homeostatic markers is observed. The patients homozygous for CSF1R mutation showed almost complete loss of microglia. The homozygous patients develop brain dysplasia, intracranial calcification, and bone malformity. Recently, mutations in NRROS, which highly expresses in microglia have been shown to cause early-onset leukoencephalopathy with the phenotype of epilepsy and mental retardation. These observations suggested that microglia plays an essential role in development and differentiation of brain and the maintenance of brain homeostasis during adulthood. The neurologic diseases caused by microglial dysfunction are now categorized as primary microgliopathy. If microglial dysfunction is primary cause of the disease(s), restoration of the microglia function may be a good therapeutic target. Based on this note, hematopoietic stem cells transplantation has been attempted in patients with ALSP, and the results of favorable outcome have been reported. The mice experiments have reported that myeloid cells may translocate into brain under pathological conditions where microglia function is impaired. Interestingly, gene expression pattern in myeloid cells translocated into brain becomes similar to those of microglia. In this symposium, I hope to dissect new aspects of microglia-related pathogenesis in the primary microgliopathy and discuss the possibility of microglia-targeted therapeutic approach.
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