據(jù)一項刊登在國際著名雜志Science Translational Medicine上新的研究報道，一種叫做RbAp48的腦蛋白含量低下可能會引起通常發(fā)生在老年人中的記憶喪失,。這些發(fā)現(xiàn)支持這樣的觀點,，即與年齡有關(guān)的記憶喪失是一種與阿爾茨海默氏癥不同的情況，并暗示經(jīng)過設(shè)計以增加該蛋白含量的療法可能會對有記憶問題的老年人有益,。
在腦中,，RbAp48通常會附著于線軸形狀的被稱作組蛋白的蛋白質(zhì)上，而DNA正是環(huán)繞并緊緊地包裹著組蛋白,，使其能夠容納于細胞核內(nèi),。然而，基因無法在如此緊湊的結(jié)構(gòu)中被激活,，因為激活所需的因子無法與基因接觸,。RbAp48可幫助組蛋白松開它們與DNA的結(jié)合，使得基因能夠得以表達,。Elias Pavlopoulos及其同事發(fā)現(xiàn),，RbAp48蛋白可特異性地協(xié)調(diào)與神經(jīng)元功能及記憶形成有關(guān)的基因表達。
研究人員從紐約哥倫比亞大學(xué)的人腦庫中獲得了8個人腦——其中有年輕人的也有老年人的,。這些人腦來自那些選擇在死后為科研捐出自己大腦的人,。將鏡頭拉近至海馬區(qū)——這是記憶形成的大腦區(qū)域，與年輕人的大腦相比,，Pavlopoulos及其同事發(fā)現(xiàn)了在老年人的腦中不能正常工作的17個基因,。這些基因特異性地位于齒狀回——這是一個被塞在海馬區(qū)內(nèi)的小回力鏢形狀的區(qū)域。
在這17個基因中,，受到影響最嚴重的基因是RbAp48,。該基因的表達以及由該基因所產(chǎn)生的RbAp48的蛋白量在老年人腦的齒狀回中減少了幾乎50%,。研究人員發(fā)現(xiàn)，在年輕小鼠中關(guān)閉該蛋白的表達會讓它們健忘,，而在老年小鼠中增加該蛋白則會恢復(fù)它們的記憶,。這些結(jié)果提示，RbAp48可能對齒狀回中的記憶形成很重要,，而老年人中的記憶喪失可能是因為腦中該蛋白含量低下所致,。還需要做進一步的研究來揭示為什么老齡化會減少腦中RbAp48的含量，并確定該蛋白是否能在人腦中成為治療的標靶,。（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
