研究表明：老年人可再拥有“年轻”大脑
2014-02-05 10:53:38 来源：37度医学网 作者： 评论：0 点击：
年龄增大与记忆力下降之间通常可画上等号。但美国一项利用小鼠进行的实验显示，这种记忆力衰退的情况并非不可“扭转”，增加一种叫做RbAp48的脑蛋白或许能让老年人再次拥有“年轻”大脑。
美国哥伦比亚大学医学中心研究人员28日在《科学—转化医学》杂志上报告说，他们从哥伦比亚大学人脑库中获得了8个人类大脑，其中有年轻人的也有老年人的，这些大脑来自那些选择在死后为科研捐脑的人。经对比研究，他们在脑记忆中心海马区中找到17个在老年人脑中不能正常工作的基因，这些基因都位于海马区中一个叫齿状回的区域。
进一步研究发现，在这17个基因中，受到衰老影响最严重的基因是RbAp48。该基因的表达以及由该基因产生的RbAp48蛋白量在老年人大脑的齿状回中减少了几乎一半。
为弄清楚RbAp48对记忆力的影响，研究人员开展了小鼠试验，结果发现，在年轻小鼠中“关闭”该蛋白会导致它们健忘，而在老年小鼠中增加该蛋白则恢复了它们的记忆。论文第一作者、哥伦比亚大学助理研究科学家埃利亚斯·帕夫洛普洛斯说：“增加蛋白不仅改善了小鼠在记忆力测试中的表现，而且其表现可与年轻小鼠相媲美，这让我们大吃一惊。”
这项成果表明，老年人中的记忆力衰退可能是因为脑中RbAp48蛋白含量低下所致，而这一过程是“可逆的”，增加该蛋白或可“扭转”老年人的记忆问题，以此蛋白为标靶将来也许能开发出新疗法。
此外，这项发现也有力表明，与年龄有关的记忆力衰退不同于阿尔茨海默氏症（又称早老性痴呆症），与年龄有关的记忆力衰退是因为神经细胞出现功能性变化，而阿尔茨海默氏症则是神经细胞大量死亡。
Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48
Abstract
To distinguish age-related memory loss more explicitly from Alzheimer’s disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation. To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation. Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.
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