TORC2: a novel target for treating age-associated memory impairment.
TORC2: a novel target for treating age-associated memory impairment.
复制标题
DOI：
10.1038/srep15193
复制
发表时间：
2015-10-22
影响因子：
4.6
通讯作者：
Costa-Mattioli M
中科院分区：
文献类型：
--
作者：
Johnson JL;Huang W;Roman G;Costa-Mattioli M
记忆力减退是21世纪最大的健康威胁之一。由于预期寿命的普遍延长，到2050年，全球20%的人口将超过60岁，与年龄有关的记忆丧失问题将急剧加剧。然而，这一不可避免的过程背后的分子机制尚不清楚。在这里，我们发现最近发现的雷帕霉素（mTOR）复合物2 （mTORC2）的机制靶点的活性在果蝇和啮齿动物的大脑中随着年龄的增长而下降，mTORC2介导的肌动蛋白聚合的丧失导致了与年龄相关的记忆丧失。有趣的是，用一种激活mTORC2 （a -443654）的小分子治疗可以逆转老年小鼠和果蝇的长期记忆（LTM）缺陷。此外，我们发现药理学上增强mTORC2或肌动蛋白聚合都能增强LTM。与目前主要针对基因表达调控（表观遗传、转录和翻译）的增强记忆的方法相反，我们的数据指向了一种依赖于结构可塑性的新的、进化上保守的恢复记忆的机制。这些对与年龄有关的记忆丧失的分子基础的见解可能为认知障碍的新治疗带来希望。
Memory decline is one of the greatest health threats of the twenty-first century. Because of the widespread increase in life expectancy, 20 percent of the global population will be over 60 in 2050 and the problems caused by age-related memory loss will be dramatically aggravated. However, the molecular mechanisms underlying this inevitable process are not well understood. Here we show that the activity of the recently discovered mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) declines with age in the brain of both fruit flies and rodents and that the loss of mTORC2-mediated actin polymerization contributes to age-associated memory loss. Intriguingly, treatment with a small molecule that activates mTORC2 (A-443654) reverses long-term memory (LTM) deficits in both aged mice and flies. In addition, we found that pharmacologically boosting either mTORC2 or actin polymerization enhances LTM. In contrast to the current approaches to enhance memory that have primarily targeted the regulation of gene expression (epigenetic, transcriptional, and translational), our data points to a novel, evolutionarily conserved mechanism for restoring memory that is dependent on structural plasticity. These insights into the molecular basis of age-related memory loss may hold promise for new treatments for cognitive disorders.