以初級培養與小鼠模式確認對阿茲海默氏症有潛力之HDAC抑制劑
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2016
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阿茲海默氏症(Alzheimer’s disease, AD)為一種常見的神經退化性疾病伴隨著出現認知功能的障礙。其病理特徵主要包括了由tau蛋白過度磷酸化所導致的神經纖維糾結(neurofibrillary tangles, NFTs)、β類澱粉蛋白質(β-amyloid peptide; Aβ)堆積造成的類澱粉斑塊(plaques)以及神經的死亡，截至目前均沒有治療的方法。表觀遺傳(Epigenetics)中組織蛋白乙醯化(histone acetylation)以及去乙醯化(histone deacetylation)能夠調控基因的表達；透過組織蛋白去乙醯(histone deacetylase, HDAC)會將組織蛋白乙醯基團移除使組織蛋白更緊密地和DNA結合，並且抑制基因的轉錄進而導致疾病的產生，而組織蛋白去乙醯酶抑制劑(histone deacetylases inhibitor, HDACi)能夠改善基因轉錄的抑制，並且已被報導在多種神經退化性疾病中扮演神經保護的作用。在本研究中，我們將Aβ25-35寡聚體藥物施於初級海馬迴神經細胞培養中造成細胞毒性以篩選具有神經保護功效之HDACi，並將有效的HDACi施用於AD小鼠驗證其可緩解神經退化之效果，透過此研究找到有潛力之HDACi，並了解分子作用機制。
在初級細胞離體實驗中我們發現NC106藥物可以增加神經突起長度(neurite length)以及神經突起分枝(branch)的數目，而且進一步發現高劑量的NC106神經保護效果較低劑量強，因此使用NC106進行動物試驗。從動物實驗中也發現高劑量的NC106在改善焦慮行為及短期記憶方面比低劑量有較強的效果，並且可以減少Aβ堆積、tau蛋白磷酸化、神經發炎反應及增加血清素神經元數目及突觸前蛋白質synaptophysin的表現量以對抗海馬迴CA1急性注射Aβ25-35寡聚體於所造成的傷害。因此，我們認為NC106是一個有潛力的AD治療藥物。
Alzheimer’s disease (AD) is a neurodegenerative disorder that cause cognitive impairment. The pathological features of AD are neurofibrillary tangles (NFTs) cause by tau protein hyper-phosphorylation,insoluble β-amyloid (Aβ) plaques by Aβ accumulation, and neuron loss.There are no curative therapies currently available for AD patients until now. The control of histone acetylation and deacetylation has been recognized as one of major epigenetic regulatory mechanisms for specific gene expression. Histone deacetylases (HDACs) make the histones more tightly by removing the acetyl groups from histones, which in turn suppresses the gene transcription and causes many diseases. It has been reported that HDAC inhibitors (HDACi) could alleviate transcription suppression and show neuroprotective effect in several neurodegenerative diseases. In thisstudy, the mouse primary hippocampal neurons treated with oligomeric Aβ25-35was used to screen potential HDAC inhibitors forAD. The identified potential HDACi compound was applied to AD miceand the molecular mechanisms of the HDACi was further elucidated.We found that NC106 HDAC inhibitor could increase neuronal numbers, neuritic length, and branch numbersagainst the oligomeric Aβ25-35-induced neurotoxicityin primary hippocampal neuronal culture. In addition, we found that the neuroprotective effects of NC106 was better in high dose than in low dose in the primary hippocampal neuronal culture treated with oligomeric Aβ25-35. The administration of high doseNC106 also attenuated the anxiety and short-term memory of the AD mice. Reducing the levels of Aβ deposition, tau protein phosphorylation, neuroinflammation, and increasing the levels of presynaptic protein synaptophysin, serotonergic neurons were identified in the B6 mice with acute bilateral intrahippocampal CA1 injection of oligomeric Aβ25-35. Therefore,NC106 could be a potential therapeutic compoundfor AD.
Alzheimer’s disease (AD) is a neurodegenerative disorder that cause cognitive impairment. The pathological features of AD are neurofibrillary tangles (NFTs) cause by tau protein hyper-phosphorylation,insoluble β-amyloid (Aβ) plaques by Aβ accumulation, and neuron loss.There are no curative therapies currently available for AD patients until now. The control of histone acetylation and deacetylation has been recognized as one of major epigenetic regulatory mechanisms for specific gene expression. Histone deacetylases (HDACs) make the histones more tightly by removing the acetyl groups from histones, which in turn suppresses the gene transcription and causes many diseases. It has been reported that HDAC inhibitors (HDACi) could alleviate transcription suppression and show neuroprotective effect in several neurodegenerative diseases. In thisstudy, the mouse primary hippocampal neurons treated with oligomeric Aβ25-35was used to screen potential HDAC inhibitors forAD. The identified potential HDACi compound was applied to AD miceand the molecular mechanisms of the HDACi was further elucidated.We found that NC106 HDAC inhibitor could increase neuronal numbers, neuritic length, and branch numbersagainst the oligomeric Aβ25-35-induced neurotoxicityin primary hippocampal neuronal culture. In addition, we found that the neuroprotective effects of NC106 was better in high dose than in low dose in the primary hippocampal neuronal culture treated with oligomeric Aβ25-35. The administration of high doseNC106 also attenuated the anxiety and short-term memory of the AD mice. Reducing the levels of Aβ deposition, tau protein phosphorylation, neuroinflammation, and increasing the levels of presynaptic protein synaptophysin, serotonergic neurons were identified in the B6 mice with acute bilateral intrahippocampal CA1 injection of oligomeric Aβ25-35. Therefore,NC106 could be a potential therapeutic compoundfor AD.
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初級海馬迴細胞培養, 組織蛋白去乙醯酶抑制劑, Aβ25-35寡聚體, 神經保護性效果, 焦慮, 短期記憶, primary hippocampal neuronal culture, histone deacetylase inhibitor, oligomeric Aβ25-35, neuroprotection, anxiety, short-term memory