据一项刊登在国际著名杂志Science Translational Medicine上新的研究报道，一种叫做RbAp48的脑蛋白含量低下可能会引起通常发生在老年人中的记忆丧失。这些发现支持这样的观点，即与年龄有关的记忆丧失是一种与阿尔茨海默氏症不同的情况，并暗示经过设计以增加该蛋白含量的疗法可能会对有记忆问题的老年人有益。
在脑中，RbAp48通常会附着于线轴形状的被称作组蛋白的蛋白质上，而DNA正是环绕并紧紧地包裹着组蛋白，使其能够容纳于细胞核内。然而，基因无法在如此紧凑的结构中被激活，因为激活所需的因子无法与基因接触。RbAp48可帮助组蛋白松开它们与DNA的结合，使得基因能够得以表达。Elias Pavlopoulos及其同事发现，RbAp48蛋白可特异性地协调与神经元功能及记忆形成有关的基因表达。
研究人员从纽约哥伦比亚大学的人脑库中获得了8个人脑——其中有年轻人的也有老年人的。这些人脑来自那些选择在死后为科研捐出自己大脑的人。将镜头拉近至海马区——这是记忆形成的大脑区域，与年轻人的大脑相比，Pavlopoulos及其同事发现了在老年人的脑中不能正常工作的17个基因。这些基因特异性地位于齿状回——这是一个被塞在海马区内的小回力镖形状的区域。
在这17个基因中，受到影响最严重的基因是RbAp48。该基因的表达以及由该基因所产生的RbAp48的蛋白量在老年人脑的齿状回中减少了几乎50%。研究人员发现，在年轻小鼠中关闭该蛋白的表达会让它们健忘，而在老年小鼠中增加该蛋白则会恢复它们的记忆。这些结果提示，RbAp48可能对齿状回中的记忆形成很重要，而老年人中的记忆丧失可能是因为脑中该蛋白含量低下所致。还需要做进一步的研究来揭示为什么老龄化会减少脑中RbAp48的含量，并确定该蛋白是否能在人脑中成为治疗的标靶。（生物谷Bioon.com）
doi:10.1126/scitranslmed.3006373
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Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48
Elias Pavlopoulos1,2,3, Sidonie Jones4,5,*, Stylianos Kosmidis1,2,3,*, Maggie Close1, Carla Kim1, Olga Kovalerchik1, Scott A. Small4,5,† and Eric R. Kandel1,2,3,†
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
