仰製腦內的PKR分子可能是治療癡呆症的關鍵

ZT:

中國科技網訊 據每日科學網近日報道，美國貝勒醫學院研究人員發現，當小鼠腦中一種名為PKR的分子活性受到抑製時，它們在學習和記憶方麵都表現得更加出色，由此可能開發出一種PKR標靶藥物來提高人們的記憶能力。相關論文發表在最近一期的《細胞》雜誌上。

    “人們隻知道PKR分子（雙鏈結構的RNA活化蛋白激酶）是一種病毒感染的感受器，對它們在大腦中的作用還一無所知。”論文高級作者、貝勒醫學院神經科學副教授莫洛·考斯特-馬蒂奧裏說，但PKR的活性在各種認知紊亂中都改變了。

    研究小組用基因技術抑製了小鼠腦中的PKR，然後訓練它們和正常小鼠尋找圓形遊泳池中的平台。結果發現，這種鼠在各種行為實驗中好像擁有了“超級”記憶。 考斯特-馬蒂奧裏解釋說：“我們發現抑製PKR能增強腦細胞的興奮性，使這些小鼠的學習和記憶能力都提高了。小鼠利用視覺線索來尋找隱藏在圓形遊泳池中的 平台，這是一種空間記憶，對於人類而言是地點和事件。在實驗中，正常小鼠必須在許多天裏經過多次重複訓練才能記住平台位置，而缺乏PKR的小鼠隻要一次訓 練就能學會。”

    他們進一步研究了這種分子過程的運作，發現當PKR被抑製時，γ幹擾素（一種與免疫力有關的分子）就會提高突觸活性，增強神經元之間的信息交流。傳統上認 為，這兩種分子隻在病毒感染和免疫反應中起作用。“沒想到它們還調控著與長期記憶形成有關的腦活動，在研究怎樣更長久地保持記憶、形成新記憶方麵扮演重要 角色。”考斯特-馬蒂奧裏說。

    此外他們還發現，PKR抑製劑（一種能鎖住PKR活性的小分子）也能模仿這一過程，因此可作為一種記憶增強藥。“這確實令人震驚，我們能用特殊的PKR標 靶藥物同時提高記憶和大腦活性。但要將此轉化為有效的療法，還需要更多研究。”考斯特-馬蒂奧裏說。他們下一步將用這些發現來提高人類的腦功能，為那些記 憶力下降的人帶來福音。

zt:

You're over the hill and — along with everything else — your memory is slipping. Your doctor gives you a pill and, suddenly, you can remember your high school locker combination.

Science fiction? Maybe not. New research out of the U.S. holds out the hope of a superhuman assist for failing memories — and a badly-needed new therapy for Alzheimer's patients.

The study by researchers at the Baylor College of Medicine in Houston — led by neuroscientist and former McGill University postdoctoral fellow Mauro Costa-Mattioli with contributions from a couple of Canadians — found suppressing a molecule called PKR in the brains of mice improved the rodents' memory function and learning abilities.

PKR is an immune molecule previously known to act as a signal to the brain of viral infections, Costa-Mattioli said.

"We recognize that PKR plays a dual role, one in regulating simple everyday processes like the way neurons talk to each other (for) memory, but also has a stress response," said John Bell, a senior scientist at the Ottawa Hospital Research Institute who also contributed to the study.

A virus is one form of stress that triggers PKR, but Alzheimer's patients' brains also experience PKR-releasing stress, said Bell, whose cancer research led him to create PKR-deficient mice which he shared with Costa-Mattioli's lab.

Researchers found that when PKR is genetically suppressed in mice, another immune molecule, called gamma interferon, increases communication between neurons, improving memory and making brain function more efficient, Costa-Mattioli said.

"If we were to find an inhibitor, a molecule, a drug that will specifically block PKR, we should be able to do the same," said Costa-Mattioli. "And we did."

Researchers injected an inhibitor into some of the mice's stomachs, finding the inhibitor worked to suppress PKR, he said. The success of the injections suggest an ingestible form of the memory-enhancing drug would likely work as well.

The study was particularly interesting because the suggestion of an interaction between PKR and gamma interferon for improved memory and learning abilities had never been made before, said Kresimir Krnjevic, a professor emeritus in neurophysiology at McGill.

Krnjevic contributed to the study, published in the Dec. 9 issue of the journal Cell, in a supporting role, giving advice and electrophysiological explanations for some of the findings.

To test the mice's memory and learning ability, researchers put them through a series of behavioural tests.

In one type of test, the mice used visual cues to find a hidden platform in a pool. It took days of repetition for the regular mice to remember where to find the platform, while the mice without PKR learned after one try.

Another type of test measured memories associated with fear that depend on contextual or auditory signals, Costa-Mattioli said.

The PKR-deficient mice were just as healthy as the normal mice, showing no increased sign of disease despite lacking the PKR immune molecule, he said. PKR plays a role in the body's response to viruses, but it's not the only signal used to warn the brain of viruses.

While a pill version of the drug is possible and would also help prevent senior citizens' fading memories, it won't be ready for at least a few years — something Costa-Mattioli said would depend on securing funding and finding a lab willing to pick up where his research left off.

The next steps would be to possibly make the drug more potent and to test its use in clinical trials, he said.

And the pill could, in theory, work on anyone, giving someone with normal brain functionality a superhuman memory, Costa-Mattioli said. But it's not what he hopes comes from his lab's discovery.

"Let's say we'd compare with Viagra. People use Viagra at whatever age, let's say 60, 65. But someone (who) is 40 goes to buy it, they can get it," he said. "But this is not our goal . . . Our goal would be to treat people who have a memory problem."

[e-mail]