仰制脑内的PKR分子可能是治疗痴呆症的关键

ZT:

中国科技网讯 据每日科学网近日报道，美国贝勒医学院研究人员发现，当小鼠脑中一种名为PKR的分子活性受到抑制时，它们在学习和记忆方面都表现得更加出色，由此可能开发出一种PKR标靶药物来提高人们的记忆能力。相关论文发表在最近一期的《细胞》杂志上。

    “人们只知道PKR分子（双链结构的RNA活化蛋白激酶）是一种病毒感染的感受器，对它们在大脑中的作用还一无所知。”论文高级作者、贝勒医学院神经科学副教授莫洛·考斯特-马蒂奥里说，但PKR的活性在各种认知紊乱中都改变了。

    研究小组用基因技术抑制了小鼠脑中的PKR，然后训练它们和正常小鼠寻找圆形游泳池中的平台。结果发现，这种鼠在各种行为实验中好像拥有了“超级”记忆。 考斯特-马蒂奥里解释说：“我们发现抑制PKR能增强脑细胞的兴奋性，使这些小鼠的学习和记忆能力都提高了。小鼠利用视觉线索来寻找隐藏在圆形游泳池中的 平台，这是一种空间记忆，对于人类而言是地点和事件。在实验中，正常小鼠必须在许多天里经过多次重复训练才能记住平台位置，而缺乏PKR的小鼠只要一次训 练就能学会。”

    他们进一步研究了这种分子过程的运作，发现当PKR被抑制时，γ干扰素（一种与免疫力有关的分子）就会提高突触活性，增强神经元之间的信息交流。传统上认 为，这两种分子只在病毒感染和免疫反应中起作用。“没想到它们还调控着与长期记忆形成有关的脑活动，在研究怎样更长久地保持记忆、形成新记忆方面扮演重要 角色。”考斯特-马蒂奥里说。

    此外他们还发现，PKR抑制剂（一种能锁住PKR活性的小分子）也能模仿这一过程，因此可作为一种记忆增强药。“这确实令人震惊，我们能用特殊的PKR标 靶药物同时提高记忆和大脑活性。但要将此转化为有效的疗法，还需要更多研究。”考斯特-马蒂奥里说。他们下一步将用这些发现来提高人类的脑功能，为那些记 忆力下降的人带来福音。

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."

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