治療老年性癡呆的潛在希望？

Potential Found in a New Approach to Alzheimer’s
治療老年癡呆的潛在希望？
By NICHOLAS WADE
By Nicholas WADE
Published: July 23, 2010紐約時報文章A potentially promising approach to treating Alzheimer’s disease has been developed by researchers studying sirtuin, a protein thought capable of extending lifespan in laboratory animals.
通過對一種可延長實驗室動物壽命的蛋白，sirtuin的研究，爲治療老年癡呆症提供了新的希望。Using mice prone to developing Alzheimer’s, the researchers showed that activating sirtuin suppressed the disease and that destroying sirtuin made it much worse. 利用老年癡呆症小鼠模型，研究人員發現，活化的sirtuin 抑制了疾病的發展，摧毀sirtuin則使得其更加糟糕。The finding was made by Gizem Donmez, Leonard Guarente and colleagues at the Massachusetts Institute of Technology, who say it raises the hope of treating Alzheimer’s, and possibly other neurodegenerative diseases like Parkinson’s and Huntington’s, with drugs that activate sirtuin. 這一研究成果是由美國麻省理工學院的Gizem Donmez,Leonard Guarente及其同事發現的，他們認爲這項研究成果爲人們利用激活sirtuin系統藥物，治療老年癡呆症、帕金森病和亨廷頓病等神經變性病的燃起了新的希望。Researchers not involved in the study agreed. “We think it is a scientifically compelling story that ties the sirtuins to the biology of Alzheimer’s disease,” said Dr. Dennis J. Selkoe, an Alzheimer’s expert at Harvard Medical School. But the therapeutic implications, Dr. Selkoe added, “remain quite up in the air.” 也有研究人員不認同這項研究，哈佛大學醫學院的老年癡呆症專家博士 Dennis J. Selkoe博士 認爲，“我們認爲這是一個科學上引人入勝的故事，將sirtuins系統和老年癡呆症生物***繫到了一起，但療效目前尚不確切。”Another expert, Dr. Juan C. Troncoso of Johns Hopkins University School of Medicine, said the finding “opens a very good avenue, but it’s not without a lot of technical challenges.”
約翰霍普金斯大學醫學院的Juan C. Troncoso博士 則認爲，這一發現“提供了一條很好的研究思路，但它其實技術挑戰多多。” Drugs that activate sirtuin already exist, including resveratrol, a minor ingredient of red wine and other foods, and small-molecule chemicals designed to mimic resveratrol. Sirtris, the company that developed the drugs, is testing them against diabetes and other diseases. This generation of drugs does not cross the blood-brain barrier so would not work against Alzheimer’s. 活化sirtuin的藥物其實已經面世，包括白藜蘆醇、紅酒、其它食物中的微小成分，模擬白藜蘆醇的低分
子化合物等。研製此類藥物的Sirtris公司正在測試其對糖尿病和其它疾病的治療作用。這種藥物無法穿
越血腦障壁，所以也不能治療老年癡呆症。But George P. Vlasuk, Sirtris’s chief executive, said the company had developed other sirtuin-activating chemicals that do reach the brain and are in preclinical trials. “We think it has very significant potential in neurodegenerative diseases,” Dr. Vlasuk said. 但是Sirtris公司的首席執行官George P. Vlasuk說，公司已研發出其他的sirtuin活化合成物，並已
進入臨牀前期試驗階段。“我們認爲這種藥物在治療神經變性疾病方面具有非常重要的潛力。”Vlasuk博
士說。 Sirtuin has been the subject of intense research in the last few years because it seems to protect the body’s various organs against disease by stepping up maintenance programs. The substance came to light through studies of longevity, particularly the discovery that reduced-calorie diets could lengthen the lifespan of mice by 30 percent. Sirtuin appears to convey much of the beneficial effect of such diets, even though drugs that activate sirtuin have not yet been shown to prolong mice’s lifespan in experiments. Sirtuin在近來數年是最熱門的研究課題，因爲其能通過更新保持系統保護機體各種器官對抗疾病。延長壽命的研究，尤其是關於低卡路里飲食可增長小鼠的壽命多達30%，使這種物質爲人所知。Sirtuin似乎傳達了許多這種飲食的益處，即便是激活sirtuin系統的藥物也無法通過實驗延長小鼠的壽命。 Dr. Guarente, a leading sirtuin researcher, said the protein’s protective power against other diseases made him wonder if it might also help against Alzheimer’s. He obtained mice that tend to develop Alzheimer’s-like symptoms because they are genetically engineered to carry two mutated human genes that cause a buildup of plaque in the brain. The mice were crossed with a strain of mice in which the sirtuin-making gene is particularly active. They were also crossed with a strain in which the sirtuin gene was deleted entirely. Dr. Guarente’s team could thus test the effect of having either more or less sirtuin in the brains of Alzheimer’s-prone mice. Guarente博士， sirtuin 研究者認爲，這種蛋白對其他疾病的保護力量使他在想是否也有助於預防老年癡呆症。他利用轉基因工程獲得了攜帶有兩個突變人類基因的老年癡呆症模型小鼠，這種突變基因可導致大腦中澱粉樣蛋白塊的沉積。這種小鼠與已活化sirtuin產生基因小鼠和敲除sirtuin基因的小鼠進行了雜交，以便測試小鼠老年癡呆模型腦中sirtuin的多少。The decline in memory typical of Alzheimer’s “was clearly suppressed” in the Alzheimer’s-prone mice with abundant sirtuin, the M.I.T. group reports in Friday’s issue of Cell, while the mice with Alzheimer’s genes and no sirtuin started to lose memory at a much younger age. 含有大量sirtuin的老年癡呆症模型小鼠記憶的下降速度被明顯的抑制了，麻省理工學院小組在週五的細胞雜誌上報道了這一發現，而無sirtuin的老年癡呆症模型小鼠在更早的時候開始喪失記憶。The team found the sirtuin protected the mice’s brains two ways. First, it activated a system called the notch pathway, which protects brain cells against stress. Second, it enhanced an enzyme whose activity avoids the buildup of the plaque characteristic of Alzheimer’s and particularly of a toxic component called A-beta peptide. 研究小組發現sirtuin通過兩種途徑保護了小鼠的大腦。 首先，它啓動了一個可以在應激條件下保護腦細胞的的系統，稱爲notch pathway。 第二，增強了抑制老年癡呆症澱粉樣蛋白塊形成酶的活性，特別如β-澱粉樣蛋白這樣的有毒成分。 Reducing the amount of A-beta peptide is helpful only in Alzheimer’s but turning on the notch pathway could provide general protection for the brain. Activating sirtuin, the M.I.T. researchers conclude, “is a viable strategy to combat Alzheimer’s disease and perhaps other neurodegenerative diseases.” 減少β-澱粉樣蛋白的數量有助於治療老年癡呆症，但激活notch pathway可以保護全腦。麻省理工的研究者總結道：活化sirtuin系統，可能是一種戰勝老年癡呆症和其他神經變性疾病的戰略。Dr. Guarente said he was looking into whether extra sirtuin had an effect in mice made vulnerable to Parkinson’s and Huntington’s disease. Activating the notch pathway with sirtuins “opens a lot of options,” Dr. Troncoso said. “If we can activate the same gene we may provide a tonic for nerve cells under stress, and that may be of use in other diseases such as Huntington’s and Parkinson’s in which the nerve cells degenerate,” he said. Guarente博士說，他正在研究是否額外的sirtuin可用於治療帕金森病和亨廷頓病模型小鼠。Troncoso博士認爲利用sirtuins激活notch pathway爲我們提供了很多選擇，“如果我們能激活相同的基因，我們可以爲應激條件下的神經細胞提供補充，並可能在如亨廷頓病和帕金森病的其他神經變性病中發揮作用。Sirtuin research is a highly active field but one whose ultimate benefit remains to be seen. The sirtuins seem to be powerful players in maintaining the body’s health, but many aspects of their behavior are still unclear. Sirtuin研究是一個非常活躍的研究領域之一，但其最終效益還有待觀察。 sirtuins似乎可用於維持人體健康，但其作用的許多方面仍然不清楚。 Also unclear is whether sirtuin’s protective effects can be elicited by drugs instead of by the usual natural stresses, like lack of nourishment. There are continuing disputes as to whether resveratrol activates sirtuin directly or indirectly. Much may depend on a Phase 2 clinical trial of resveratrol with Type 2 diabetes. The results of the trial should be known later in the year, Dr. Vlasuk said in an interview last month. 目前尚不清楚，sirtuin的保護作用除了通過被諸如營養缺乏這樣的自然應激事件所激活，是否還可以被藥物誘發。白藜蘆醇到底是通過直接或間接途徑激活sirtuin，目前尚存在爭議。更多的需要等待2型糖尿病2期臨牀試驗的結果，這一結果將會在今年晚些時候出爐，Vlasuk博士上個月接受採訪時表示。Should resveratrol prove ineffective, Sirtris has two small-molecule chemical drugs, known as 2104 and 2379, which are also in clinical trials. The chemicals can be given in much smaller doses than resveratrol. There have been no safety issues with any of the drugs, Dr. Vlasuk said, with the possible exception of a multiple myeloma trial, using very high doses of resveratrol, in which several patients developed a symptom common with the disease. The trial ceased new enrollment of patients in May.如果白藜蘆醇證明無效，Sirtri公司還有兩個其他的小分子化學藥物，編號2104和2379，也已經進入臨牀試驗，這些合成物的有效劑量比白藜蘆醇劑量小得多。這些藥物都沒有安全保證，Vlasuk博士說，除了一個例外的多發性骨髓瘤試驗，使用大劑量的白藜蘆醇，其中有幾名患者出現了與此疾病相同的症狀。該試驗在5月停止新的病人註冊。