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老年癡呆病因新證

In Preventing Alzheimer’s, Mutation May Aid Drug Quest
老年癡呆病因新證

Two decades ago, researchers began discovering rare gene mutations that cause Alzheimer’s disease in all who inherit them. Now, they have found the opposite: a mutation that prevents the devastating brain disorder. The protective mutation also is very rare — it is not the reason most people do not develop Alzheimer’s disease. But what intrigues researchers is how it protects the brain. It does the reverse of what the mutations that cause Alzheimer’s do. Those mutations lead to excessive amounts of a normal substance, beta amyloid, in the brain. The protective mutation slows beta amyloid production, so people make much less.

20年前,研究人員第一次發現罕見的基因突變導致了老年癡呆癥(阿爾茲海默?。?。而如今,他們發現,有一種基因突變能夠防止這種毀滅性的大腦功能紊亂。這種防護性突變也很罕見,因而并非大多數人不患老年癡呆癥的原因。但是讓研究人員感興趣的是它保護大腦的方式。那些致病的基因突變導致腦中的正常元素乙型淀粉樣蛋白過量從而引發了老年癡呆癥。與此相反,防護性基因突變會減緩淀粉樣蛋白的生成,因而減少其總量。

The discovery, published online on Wednesday in the journal Nature, provides strong evidence that beta amyloid buildup is a driving force in this destructive brain disease. It also bolsters the hopes of drug companies that have zealously developed drugs to reduce amyloid levels with the expectation they might alter the course of the disease or even prevent it. So far, the drugs have not succeeded, but companies and many researchers have argued that there are reasons for that and that it is too soon to give up on them.

這項發現于周三被發表在《自然》(Nature)的網絡版上,它為證明淀粉樣蛋白過多是導致這種破壞性腦部疾病的主因提供了有力證據。這也為那些積極研發降低乙型淀粉樣蛋白含量藥物的制藥公司帶來了希望,他們期待自己的藥物能夠改變發病過程,甚至是防止疾病的發生。到目前為止,這類藥物還沒有獲得成功,但是制藥公司和許多研究人員辯稱,這其中有著很多原因,因而不能輕言放棄。
 

If for no other reason, the discovery’s implication for drug development “is hugely important,” said Dr. David Altshuler, a genomics expert at Harvard Medical School and the Broad Institute of Harvard and M.I.T. who was not involved with the research.

即便沒有其他原因,這項發現對于藥物開發“意義巨大”,戴維·阿特舒勒(David Altshuler) 博士稱。他是哈弗大學醫學院(Harvard Medical School)及布洛德 研究所(the Broad Institute of Harvard and M.I.T.)的基因組學專家,但并未參與這項研究。

It indicates, he said, that drug companies’ big bets on anti-amyloid treatments could pay off.

他表示,制藥公司在抗淀粉蛋白的治療藥物上下了巨大賭注,而這項研究結果表明,他們很可能會有所收獲。

“This paper provides strong evidence that it would work in the general population if you did it right,” Dr. Altshuler said.

“這份研究結果提供了強有力的證據,證明了如果操作正確,這種藥物可以適用于普通人群,”阿特舒勒博士說。

Dr. Samuel Gandy, an Alzheimer’s researcher who directs the Mount Sinai Center for Cognitive Health, had a similar response, calling the finding “extraordinarily important” — the most significant in the field since researchers first reported a mutation that leads to the disease, 22 years ago.

主管西奈山醫學院認知健康中心(Mount Sinai Center for Cognitive Health)的塞繆爾·甘迪(SamuelGandy)博士的研究領域也是老年癡呆癥。他給出了類似的回應,稱這項研究結果“極為重要”,是22年前研究人員首次發現基因突變導致老年癡呆癥以來該領域的最顯著研究成果。

The discovery of the protective gene mutation, a product of the revolution that has taken place in genetics, arose when researchers scanned the entire DNA of 1,795 Icelanders. About one in 100 had a mutation in the gene for a large protein that is sliced to form beta amyloid. Then the investigators studied people ages 85 and older and people who had been given an Alzheimer’s diagnosis. Those with the mutation appeared to be protected from Alzheimer’s disease. The investigators, led by Dr. Kari Stefansson, chief executive at DeCode Genetics, an Icelandic company, then looked at genomes of North Americans and found the gene mutation in only about one in 10,000 people. That indicates, Dr. Stefansson said, that the mutation arose relatively recently in Scandinavia.

研究人員在掃描檢查1795個冰島人的全部DNA時發現了這個防護性基因突變。這也是基因學領域的變革所帶來的成果。大約每一百個人中,有一個人體內負責將大型蛋白質分化為乙型淀粉樣蛋白的基因發生突變。之后,研究人員對年滿85歲的人群與老年癡呆癥患者進行研究。他們發現身體存在這種突變的人似乎因此受到保護而不患老年癡呆癥。由冰島基因解碼公司(DeCode Genetics)首席執行官卡里·斯蒂芬森(KariStefansson)博士帶領的研究團隊隨后研究了北美洲人群的基因組,他們發現一萬人當中只有一個人有這種基因突變。斯蒂芬森博士表示,研究結果說明這種基因突變發生在在斯堪的納維亞,而且時間較晚。

The protective gene even appears to override a very strong risk factor for Alzheimer’s disease in old age — two copies of a gene known as ApoE4. Ninety percent of people with two ApoE4 genes get Alzheimer’s by age 80. But Dr. Stefansson says there are 25 people in his study with two copies of ApoE4. None have Alzheimer’s disease.

這種防護性基因甚至似乎能夠壓制導致老年人患老年癡呆癥高風險基因,即ApoE4基因的兩個變體。90%擁有這兩種ApoE4基因的人會在80歲之前患上老年癡呆癥。斯蒂芬森博士說,研究人群中的25人擁有這兩種ApoE4基因變體,但他們并未患上老年癡呆癥。

The research “is obviously right,” said John Hardy, an Alzheimer’s researcher at University College London and a discoverer of the first gene mutation found to cause the disease. “The statistics and the finding are pretty secure.”

作為第一例致病基因突變的發現者,英國倫敦大學學院(University College London)的老年癡呆癥專家約翰·哈迪(JohnHardy)表示,這項研究“顯然是正確的,其數據與結果都相當可靠。”

The discovery is part of a continuing story that implicates beta amyloid as a central and crucial player in this destructive brain disease. The idea began two decades ago with the discovery of very rare gene mutations that always cause Alzheimer’s in those who inherit them, usually by middle age. The mutations were different in different families, but all had the same effect: They increased the amount of beta amyloid in the brain. That meant that a buildup of amyloid was sufficient to cause the disease.

發現淀粉樣蛋白在這種破壞性腦部疾病中扮演關鍵角色是一個漫長的研究過程,而這項研究結果只是其中一部分。這方面的研究開始于20年前。當時,研究人員發現,有一種人必定會患上老年癡呆癥,而這些人都繼承了一種非常罕見的突變基因,他們往往是人到中年就已發病。這種突變在不同的家族中表現不一,但是他們都有相同的結果,即增加了腦部乙型淀粉樣蛋白的含量。這意味著腦部淀粉樣蛋白的積累足以致病。

Elderly people with Alzheimer’s — who typically did not have these gene mutations — also had excess amyloid in the brain. So, researchers reasoned, that might mean that excess amyloid was causing the disease in them too.

那些患老年癡呆癥的年長人士通常沒有突變基因,但他們的腦部都含有過量的淀粉樣蛋白。所以,研究人員分析,這可能意味著他們患病也是由淀粉樣蛋白過量引起的。

Researchers and drug companies have focused on the amyloid hypothesis to the extent that almost every experimental drug being tested to slow or halt Alzheimer’s disease is designed to reduce the amount of amyloid in the brain.

研究人員和制藥公司將大量精力集中在淀粉樣蛋白假說上,這導致幾乎所有用來減緩或防止老年癡呆癥的實驗性藥物都是通過減少腦部淀粉樣蛋白來發揮作用的。

As provocative as the discovery of the protective gene mutation is, the strategy of reducing amyloid levels — the ultimate test of the amyloid hypothesis — still must be evaluated in typical Alzheimer’s disease. For example, perhaps people need to have lower levels of beta amyloid from birth to really be protected from Alzheimer’s disease.

雖然發現防護性基因突變令人激動,降低淀粉樣蛋白水平的策略——淀粉樣蛋白假說的最終考驗——仍然必須在典型的老年癡呆癥患者身上進行評估。比如,也許只有從出生起就具有較低水平的淀粉樣蛋白才能最終免于患上老年癡呆癥。

Researchers and companies explain away the failure of the first few experimental drugs to reduce beta amyloid levels or to block the protein by saying they were not powerful enough and were studied in people who already had the disease and clear symptoms of mental decline. By then it might be too late to make any difference. When brain cells have died, nothing can bring them back.

研究人員和制藥公司解釋稱,最初的幾種實驗性藥物之所以未能成功地降低腦部淀粉蛋白水平和限制蛋白質的產生,是因為藥性不夠強,而且藥物是在那些已經患有老年癡呆癥,智力明顯下降的人群中試用的。在那一階段,藥物可能已經無法引起改變。腦細胞的死亡是不可逆轉的。

The strategy now is to use new brain scans and other methods to find and treat people before they have symptoms of mental decline.

現在的新策略是,研究人員通過新的腦部掃描和其他方法鎖定相關人群,并在他們的智力開始下降之前對其展開治療。

“The idea is that treatment has to start early to make a difference,” said Ryan Watts, a neurodegeneration researcher at the drug company Genentech.

“現在的想法是。病人必須及早治療, 這樣才會有效果,”制藥公司基因泰克(Genentech)的神經性退變研究人員瑞安·沃茨(RyanWatts)說。
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