在3月26日網(wǎng)絡(luò)版Proceedings of the National Academy of Sciences發(fā)表的文章中,，加利福尼亞大學(xué)圣地亞哥醫(yī)學(xué)院的研究人員指出,，反復(fù)應(yīng)激觸發(fā)小鼠腦細(xì)胞內(nèi)不溶性tau蛋白聚集體的生產(chǎn)和堆積。
聚合體類(lèi)似于神經(jīng)纖維纏結(jié)(NFTs),，一種修改的蛋白質(zhì)結(jié)構(gòu),，是阿爾茨海默病的一種生理標(biāo)志,。該發(fā)現(xiàn)至少部分解釋了臨床研究為什么發(fā)現(xiàn)容易緊張的人與散發(fā)型阿爾茨海默氏?。ˋD）發(fā)生之間的密切聯(lián)系，其中散發(fā)型阿爾茨海默氏病占所有老年癡呆癥病例的95%,。
在小鼠模型中,，研究人員發(fā)現(xiàn)，日常生活中可能經(jīng)歷的反復(fù)的情感應(yīng)激事件導(dǎo)致神經(jīng)元中tau蛋白質(zhì)的磷酸化和可溶性改變,，而這些事件對(duì)于阿爾茨海默氏病NFT病理學(xué)的發(fā)展是至關(guān)重要的,。該作用在與記憶形成、組織和貯存相關(guān)的海馬中最顯著,。在A(yíng)D患者中,，海馬是典型的第一個(gè)受tau病理和大量細(xì)胞死亡與收縮重?fù)粲绊懙拇竽X區(qū)域。并不是所有形式的緊張都具有相同的威脅作用,。既往研究指出,，急性應(yīng)激（單一的一過(guò)性事件）不會(huì)導(dǎo)致磷化tau蛋白累積上的持久性、逐漸減弱的長(zhǎng)期變化?？傮w上,，急性應(yīng)激誘導(dǎo)的細(xì)胞改變是暫時(shí)的，可能是有益的,。
急性應(yīng)激可能對(duì)大腦可塑性有用,，有助于易化學(xué)習(xí)。慢性應(yīng)激和應(yīng)激通路的連續(xù)激活可能導(dǎo)致形成應(yīng)激回路的病理改變,。人隨著年齡增加,，他們的神經(jīng)回路也許激活得太多以致變得不再?gòu)?qiáng)健，也許不能從應(yīng)激效應(yīng)中完全復(fù)原,。
研究發(fā)現(xiàn),，應(yīng)激影響兩個(gè)關(guān)鍵的促皮質(zhì)釋放素受體，意味著它們很可能是潛在治療方法的靶標(biāo),。我們不能排除應(yīng)激,，必需能對(duì)應(yīng)激刺激有不同水平的反應(yīng)。但可以用拮抗分子減少神經(jīng)元的應(yīng)激效應(yīng),。應(yīng)激系統(tǒng)還能反應(yīng),，但是可調(diào)低大腦和海馬的反應(yīng)，以便不形成有害的永久性損傷,。（生物谷bioon.com）
doi:10.1073/pnas.1203140109
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Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation
Robert A. Rissman, Michael A. Staup, Allyson Roe Lee, Nicholas J. Justice, Kenner C. Rice, Wylie Vale, and Paul E. Sawchenko
Exposure and/or sensitivity to stress have been implicated as conferring risk for development of Alzheimer's disease (AD). Although the basis for such a link remains unclear, we previously reported differential involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 in acute stress-induced tau phosphorylation (tau-P) and solubility in the hippocampus. Here we examined the role of CRFRs in tau-P induced by repeated stress and the structural manifestations of altered tau solubility. Robust tau-P responses were seen in WT and CRFR2 null mice exposed to repeated stress, which were sustained at even 24 h after the final stress exposure. A portion of phosphorylated tau in these mice was sequestered in detergent-soluble cellular fractions. In contrast, CRFR1 and CRFR double-KO mice did not exhibit repeated stress-induced alterations in tau-P or solubility. Similarly, treatment with CRFR1 antagonist attenuated repeated stress-induced tau-P. Using histochemical approaches in a transgenic CRFR1 reporter mouse line, we found substantial overlap between hippocampal CRFR1 expression and cells positive for phosphorylated tau after exposure to repeated stress. Ultrastructural analysis of negatively stained extracts from WT and CRFR2 null mice identified globular aggregates that displayed positive immunogold labeling for tau-P, as well as conformational changes in tau (MC1) seen in early AD. Given that repeated stress exposure results in chronic increases in hippocampal tau-P and its sequestration in an insoluble (and potentially prepathogenic) form, our data may define a link between stress and an AD-related pathogenic mechanism.
